This article discusses emerging evidence that signals from apoptotic and old/dysfunctional osteocytes contribute to the pathogenesis of common forms of osteoporosis like involutional, post-menopausal, and glucocorticoid-induced osteoporosis. Osteocytes are long-lived cells embedded in bone that form an extensive communication network. As the most abundant cell type in bone, osteocytes are well-positioned to detect changes in bone and coordinate the bone remodeling process through controlling osteoclast formation via RANKL and osteoblast formation via sclerostin. The article suggests that as osteocytes age and die, their distress signals may initiate an imbalance in bone remodeling leading to increased bone fragility and osteop
This document summarizes research on communication between osteoblasts and osteoclasts, the two main cells involved in bone remodeling. It discusses how osteoblasts can affect osteoclast formation and differentiation through several pathways, such as OPG/RANKL/RANK, ephrin2/ephB4, and M-CSF. It also reviews how osteoclasts can influence osteoblast activity through factors like Atp6v0d2. Direct cell-cell contact and cytokines released from resorbed bone matrix also facilitate communication between osteoblasts and osteoclasts. Imbalances in this communication can lead to bone diseases like osteoporosis.
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Role of osteoclasts in periodontal health and diseaseVarun Dhanankula
Osteoclasts are large, multinucleated cells that originate from hematopoietic tissue and function to break down bone through secretion of hydrolytic enzymes. In periodontal health, osteoclasts work with osteoblasts to remodel bone through formative and remodeling functions, maintaining bone shape and homeostasis. In periodontal disease, osteoclast activity is increased, leading to bone destruction through two main mechanisms - trauma from occlusion exacerbating inflammation-induced bone loss, and influences from systemic factors like age, osteoporosis, and hormones on the osteoclast-osteoblast balance.
This document provides an overview of the structure of bone. It begins by classifying bones based on their location in the body, shape, size, texture, matrix arrangement, maturity, and developmental origin. It then discusses the composition, anatomy, microscopic structure, histogenesis, dynamics, functions, calcium and phosphate metabolism, mineralization, blood supply, and development of facial bones in detail across multiple sections. The document is a comprehensive review of the structure and properties of bone intended to educate readers on this important tissue.
This document discusses the structure and functions of bone and skeletal tissue. It provides details on:
- The basic structure of long bones including diaphysis, epiphyses, and metaphyses.
- The histology of bone tissue, which is made up of an extracellular matrix containing collagen fibers and mineral salts surrounding osteocytes.
- How bones form through two processes - intramembranous ossification which forms flat bones, and endochondral ossification which forms most bones including long bones.
- How bones grow in length via growth at the epiphyseal plate and how remodeling of bone occurs throughout life to replace old bone.
The skeletal system document summarizes key aspects of bone structure and function. It describes how bone is composed of mineral and organic components including collagen fibers. It discusses how aging affects bone remodeling and loss of bone density. It also outlines interventions that can help slow bone loss such as hormone therapy, medications, diet and exercise. Diagrams illustrate bone density changes with aging and risks of fracture.
The document discusses the structure and function of bones. It describes that bones are composed of cells embedded in a calcified matrix. The main cell types are osteoprogenitor cells, osteoblasts, osteoclasts and osteocytes. Bone has two types of osseous tissue - compact bone and spongy bone. Compact bone has concentric lamellae surrounding Haversian canals, while spongy bone has a more porous structure. Bones provide structure, protection, enable movement and store minerals. Remodeling and modeling allow bones to adapt throughout life.
Bone death in osteoarthritis is extensively studied but not fully understood. Subchondral bone ischemia may play an important role by reducing blood flow and nutrient diffusion. This can lead to osteocyte death, bone resorption, and lack of bony support for overlying cartilage. Disruption of the normal bone-cartilage interface through osteonecrosis may represent a cause rather than just a result of osteoarthritis progression. Maintaining adequate subchondral bone perfusion may be important for preventing cartilage degeneration in osteoarthritis.
This document summarizes research on communication between osteoblasts and osteoclasts, the two main cells involved in bone remodeling. It discusses how osteoblasts can affect osteoclast formation and differentiation through several pathways, such as OPG/RANKL/RANK, ephrin2/ephB4, and M-CSF. It also reviews how osteoclasts can influence osteoblast activity through factors like Atp6v0d2. Direct cell-cell contact and cytokines released from resorbed bone matrix also facilitate communication between osteoblasts and osteoclasts. Imbalances in this communication can lead to bone diseases like osteoporosis.
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Role of osteoclasts in periodontal health and diseaseVarun Dhanankula
Osteoclasts are large, multinucleated cells that originate from hematopoietic tissue and function to break down bone through secretion of hydrolytic enzymes. In periodontal health, osteoclasts work with osteoblasts to remodel bone through formative and remodeling functions, maintaining bone shape and homeostasis. In periodontal disease, osteoclast activity is increased, leading to bone destruction through two main mechanisms - trauma from occlusion exacerbating inflammation-induced bone loss, and influences from systemic factors like age, osteoporosis, and hormones on the osteoclast-osteoblast balance.
This document provides an overview of the structure of bone. It begins by classifying bones based on their location in the body, shape, size, texture, matrix arrangement, maturity, and developmental origin. It then discusses the composition, anatomy, microscopic structure, histogenesis, dynamics, functions, calcium and phosphate metabolism, mineralization, blood supply, and development of facial bones in detail across multiple sections. The document is a comprehensive review of the structure and properties of bone intended to educate readers on this important tissue.
This document discusses the structure and functions of bone and skeletal tissue. It provides details on:
- The basic structure of long bones including diaphysis, epiphyses, and metaphyses.
- The histology of bone tissue, which is made up of an extracellular matrix containing collagen fibers and mineral salts surrounding osteocytes.
- How bones form through two processes - intramembranous ossification which forms flat bones, and endochondral ossification which forms most bones including long bones.
- How bones grow in length via growth at the epiphyseal plate and how remodeling of bone occurs throughout life to replace old bone.
The skeletal system document summarizes key aspects of bone structure and function. It describes how bone is composed of mineral and organic components including collagen fibers. It discusses how aging affects bone remodeling and loss of bone density. It also outlines interventions that can help slow bone loss such as hormone therapy, medications, diet and exercise. Diagrams illustrate bone density changes with aging and risks of fracture.
The document discusses the structure and function of bones. It describes that bones are composed of cells embedded in a calcified matrix. The main cell types are osteoprogenitor cells, osteoblasts, osteoclasts and osteocytes. Bone has two types of osseous tissue - compact bone and spongy bone. Compact bone has concentric lamellae surrounding Haversian canals, while spongy bone has a more porous structure. Bones provide structure, protection, enable movement and store minerals. Remodeling and modeling allow bones to adapt throughout life.
Bone death in osteoarthritis is extensively studied but not fully understood. Subchondral bone ischemia may play an important role by reducing blood flow and nutrient diffusion. This can lead to osteocyte death, bone resorption, and lack of bony support for overlying cartilage. Disruption of the normal bone-cartilage interface through osteonecrosis may represent a cause rather than just a result of osteoarthritis progression. Maintaining adequate subchondral bone perfusion may be important for preventing cartilage degeneration in osteoarthritis.
Healing of Bone - Dr. Shweta Yadav - Oral and Maxillofacial SurgeryDr. Shweta Yadav
Bone healing is a complex process that occurs in multiple stages to restore injured bone. It involves inflammation, cell proliferation, callus formation, consolidation, and remodeling. There are two main types: healing by direct union, which occurs when fracture ends are close together; and healing by callus formation, which involves five stages over several months. Many local and systemic factors can influence bone healing, and treatment aims to properly position fragments, stabilize fractures, and use grafting when needed. Complications include malunion, delayed healing, non-union, and infection.
This document discusses metabolic bone diseases. It begins by describing the basic structure and function of bone, including its cellular components like osteoblasts and osteoclasts. It then discusses the constituents of bone matrix, including collagen, proteoglycans, and minerals. Bone development and homeostasis are explained, involving processes like remodeling. Specific metabolic bone diseases are then outlined in more detail, including osteogenesis imperfecta (brittle bone disease), osteomalacia/rickets due to abnormal mineralization, and hypophosphatasia due to a genetic disturbance in alkaline phosphatase synthesis. Throughout, the document provides microscopic and radiographic characteristics of these conditions.
This document summarizes the process of distraction osteogenesis, which involves surgically separating bone segments and using an external fixator to slowly pull the segments apart, inducing new bone growth in the gap. It describes the three phases of distraction osteogenesis - the latent phase involving inflammation and recruitment of stem cells; the distraction phase where mechanical strain promotes new bone formation; and the consolidation phase where the new bone matures. Key cellular processes involving osteoblasts and osteoclasts during bone formation and remodeling are also summarized. Potential future approaches to improve distraction osteogenesis outcomes through modulating these cells are outlined.
Bone loss occurs when resorption exceeds formation due to an imbalance between inflammatory and anti-inflammatory signals. Bacterial products stimulate immune cells like macrophages and T cells to release cytokines that promote osteoclast formation through the RANKL pathway. Mature osteoclasts attach to bone and secrete acids and enzymes to degrade the mineralized matrix and organic components. While inflammatory mediators increase resorption, anti-inflammatory cytokines from T cells and other cells inhibit osteoclasts and support new bone formation to maintain equilibrium. Periodontitis results from this inflammatory process overwhelming the protective mechanisms and leading to net bone destruction.
The document summarizes the mechanism of alveolar bone destruction in periodontitis. It discusses the structure of alveolar bone and the process of bone remodeling which is regulated by factors that control bone resorption and formation. Key cytokines like IL-1, IL-6, TNF-α play a role in bone resorption by stimulating osteoclastogenesis directly or indirectly via prostaglandins. The balance between these resorptive and formative factors is important in maintaining bone homeostasis, and an imbalance leads to periodontal bone loss.
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Osteoporosis: Classification, Causes, Symptoms, Treatment & Prevention
In this article, we’ll discuss what osteoporosis is, osteoporosis definition, osteoporosis types, osteoporosis causes, osteoporosis symptoms, osteoporosis medicine, osteoporosis treatment and osteoporosis prevention.
Osteoporosis:
Osteoporosis is a condition of low bone mass and decay of bone tissue prompting bone delicacy and conceivably breaking with numerous preventable and intrinsic danger factors. Osteoporosis influences bones and makes them more defenseless against sudden and unanticipated breaks and breakage. The term osteoporosis is derived from the Greek words osteon (bone) and poros (pore). For complete article, click on the given link, https://diseases8804.blogspot.com/2021/08/all-you-need-to-learn-about-osteoporosis.html
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.
The human skeleton consists mainly of cortical and trabecular bone. There are three main types of bone cells - osteocytes, osteoclasts, and osteoblasts. Osteoblasts form new bone, osteoclasts resorb bone, and osteocytes maintain bone structure. Bones provide structure, protection, storage, and leverage. Hormones like estrogen, calcitonin, parathyroid hormone, and thyroxine regulate bone metabolism. Vitamin D and calcium are important for bone health and absorption. Osteoporosis occurs when bone resorption exceeds formation, decreasing bone density and strength and increasing fracture risk. It is diagnosed using DEXA scans and treated with supplements, bisphosphonates,
The document discusses biochemical markers of bone turnover. It notes that in adults, bone undergoes constant remodeling through resorption by osteoclasts and formation by osteoblasts. Biochemical markers measure bone formation or resorption products in blood and urine, allowing serial assessment of bone turnover. Formation markers include osteocalcin and procollagen peptides, while resorption markers include collagen telopeptides and hydroxypyridinium cross-links. These markers can help evaluate treatment response, predict fracture risk and bone loss, and select patients who may benefit most from treatment. However, markers have limitations due to biological and analytical variability.
Osteoblasts form new bone tissue and regulate mineral deposition on bone surfaces. Osteoclasts degrade and resorb bone tissue. Osteocytes were formerly osteoblasts embedded in the bone matrix and communicate with other bone cells to regulate bone remodeling and respond to mechanical stresses on bones.
This document provides an overview of bone histology and development. It discusses that bone is a specialized mineralized connective tissue that can be divided into compact and cancellous bone microscopically. Bone develops through either endochondral or intramembranous ossification. The key cells involved are osteoblasts, which form new bone, and osteoclasts, which resorb bone. Bone is remodeled throughout life by the balanced actions of these cells.
Miacalcic Training 2004 Platform Syr April 03haithamo
The document provides information about MIACALCIC® Nasal Spray, a treatment for post-menopausal osteoporosis. It discusses the development and approval of the nasal spray formulation of calcitonin-salmon for this indication. It also provides background information on osteoporosis prevalence, risk factors, consequences such as fractures, and the role of bone remodeling and calcium homeostasis in the disease.
Bone is a specialized connective tissue composed of both organic and inorganic parts. The organic part includes collagen and other proteins, while the inorganic part contains calcium and phosphate minerals. Bone contains three main cell types - osteoprogenitor cells that develop into osteoblasts or osteoclasts. Osteoblasts form new bone by secreting proteins and minerals, osteoclasts break down bone, and osteocytes maintain bone structure. Together these cells regulate bone remodeling through signals that stimulate or inhibit each other's activity.
This document discusses the anatomy and structure of alveolar bone. It begins by classifying bone and describing its composition and functions. It then focuses on the specific properties of alveolar bone, including that it develops from the dental follicle and supports tooth roots. The key cellular and structural elements of alveolar bone are described, such as bone cells, bone matrix, Sharpey's fibers, and blood supply. In summary, the document provides an overview of the development, functions, cellular components, and vascular features of the specialized alveolar bone that surrounds and supports teeth.
Bone is a living tissue that provides structure and support. It can be classified based on shape, development, histology, and composition. The alveolar process forms with tooth development and eruption to support teeth in the jaw. It consists of cortical and cancellous bone layers surrounded by osteoblasts and osteoclasts, which build and resorb bone through various signaling pathways and enzymes.
This document provides an overview of bone formation, resorption, and remodeling. It discusses the classification of bones based on shape and development. It describes the composition of bone including cells like osteoblasts, osteoclasts, and osteocytes. Bone formation is mediated by growth factors while resorption involves acid secretion and enzyme activity by osteoclasts. Remodeling is a continuous process where old bone is replaced, maintaining bone strength through the coupled activities of formation and resorption. Markers of bone turnover provide information about these dynamic processes.
There are two main types of osteoporosis: primary and secondary. Primary osteoporosis is more common in post-menopausal women and affects those over 50, causing the loss of bone density as aging causes bone breakdown to outpace bone formation. Secondary osteoporosis is caused by an underlying health condition or medication that directly or indirectly decreases bone density and increases osteoporosis risk later in life.
The document discusses the development and structure of alveolar bone. It notes that alveolar bone develops from the dental follicle, where ectomesenchymal cells differentiate into osteoblasts that lay down bone matrix. Alveolar bone is composed of two parts: the alveolar bone proper that lines the tooth sockets, and the supporting bone below it. The alveolar bone proper appears as the lamina dura on radiographs and is resorbed during tooth movement. The supporting bone includes compact cortical plates and spongy cancellous bone between the plates and alveolar bone proper.
Marine VHF radio is used for rescue communication by vessels at sea. It operates between 156-162 MHz and uses frequency modulation. Newer models have additional features like digital selective calling and weather broadcasts. Selectivity is the ability to receive desired signals clearly when traffic is high. Higher selectivity is needed in busy areas and provided by fixed-mount versus handheld radios. Key considerations for marine VHF radios include weather resistance, performance in high traffic, and a provider with quality products.
Marine VHF radio is one such instrument that is in use for decades to avoid collision in sea and direct vessels in the right direction. These radios are used as an aid to keep you on the right track and call for aid when in distress. These radios operate on very high frequencies i.e. between 156 MHz to 162 MHz dedicated for marine communication. For further information about marine vhf radios visit: http://www.sailradios.com/Marine-Communication-VHF-Radios-s/1825.htm
Healing of Bone - Dr. Shweta Yadav - Oral and Maxillofacial SurgeryDr. Shweta Yadav
Bone healing is a complex process that occurs in multiple stages to restore injured bone. It involves inflammation, cell proliferation, callus formation, consolidation, and remodeling. There are two main types: healing by direct union, which occurs when fracture ends are close together; and healing by callus formation, which involves five stages over several months. Many local and systemic factors can influence bone healing, and treatment aims to properly position fragments, stabilize fractures, and use grafting when needed. Complications include malunion, delayed healing, non-union, and infection.
This document discusses metabolic bone diseases. It begins by describing the basic structure and function of bone, including its cellular components like osteoblasts and osteoclasts. It then discusses the constituents of bone matrix, including collagen, proteoglycans, and minerals. Bone development and homeostasis are explained, involving processes like remodeling. Specific metabolic bone diseases are then outlined in more detail, including osteogenesis imperfecta (brittle bone disease), osteomalacia/rickets due to abnormal mineralization, and hypophosphatasia due to a genetic disturbance in alkaline phosphatase synthesis. Throughout, the document provides microscopic and radiographic characteristics of these conditions.
This document summarizes the process of distraction osteogenesis, which involves surgically separating bone segments and using an external fixator to slowly pull the segments apart, inducing new bone growth in the gap. It describes the three phases of distraction osteogenesis - the latent phase involving inflammation and recruitment of stem cells; the distraction phase where mechanical strain promotes new bone formation; and the consolidation phase where the new bone matures. Key cellular processes involving osteoblasts and osteoclasts during bone formation and remodeling are also summarized. Potential future approaches to improve distraction osteogenesis outcomes through modulating these cells are outlined.
Bone loss occurs when resorption exceeds formation due to an imbalance between inflammatory and anti-inflammatory signals. Bacterial products stimulate immune cells like macrophages and T cells to release cytokines that promote osteoclast formation through the RANKL pathway. Mature osteoclasts attach to bone and secrete acids and enzymes to degrade the mineralized matrix and organic components. While inflammatory mediators increase resorption, anti-inflammatory cytokines from T cells and other cells inhibit osteoclasts and support new bone formation to maintain equilibrium. Periodontitis results from this inflammatory process overwhelming the protective mechanisms and leading to net bone destruction.
The document summarizes the mechanism of alveolar bone destruction in periodontitis. It discusses the structure of alveolar bone and the process of bone remodeling which is regulated by factors that control bone resorption and formation. Key cytokines like IL-1, IL-6, TNF-α play a role in bone resorption by stimulating osteoclastogenesis directly or indirectly via prostaglandins. The balance between these resorptive and formative factors is important in maintaining bone homeostasis, and an imbalance leads to periodontal bone loss.
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Osteoporosis: Classification, Causes, Symptoms, Treatment & Prevention
In this article, we’ll discuss what osteoporosis is, osteoporosis definition, osteoporosis types, osteoporosis causes, osteoporosis symptoms, osteoporosis medicine, osteoporosis treatment and osteoporosis prevention.
Osteoporosis:
Osteoporosis is a condition of low bone mass and decay of bone tissue prompting bone delicacy and conceivably breaking with numerous preventable and intrinsic danger factors. Osteoporosis influences bones and makes them more defenseless against sudden and unanticipated breaks and breakage. The term osteoporosis is derived from the Greek words osteon (bone) and poros (pore). For complete article, click on the given link, https://diseases8804.blogspot.com/2021/08/all-you-need-to-learn-about-osteoporosis.html
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.
The human skeleton consists mainly of cortical and trabecular bone. There are three main types of bone cells - osteocytes, osteoclasts, and osteoblasts. Osteoblasts form new bone, osteoclasts resorb bone, and osteocytes maintain bone structure. Bones provide structure, protection, storage, and leverage. Hormones like estrogen, calcitonin, parathyroid hormone, and thyroxine regulate bone metabolism. Vitamin D and calcium are important for bone health and absorption. Osteoporosis occurs when bone resorption exceeds formation, decreasing bone density and strength and increasing fracture risk. It is diagnosed using DEXA scans and treated with supplements, bisphosphonates,
The document discusses biochemical markers of bone turnover. It notes that in adults, bone undergoes constant remodeling through resorption by osteoclasts and formation by osteoblasts. Biochemical markers measure bone formation or resorption products in blood and urine, allowing serial assessment of bone turnover. Formation markers include osteocalcin and procollagen peptides, while resorption markers include collagen telopeptides and hydroxypyridinium cross-links. These markers can help evaluate treatment response, predict fracture risk and bone loss, and select patients who may benefit most from treatment. However, markers have limitations due to biological and analytical variability.
Osteoblasts form new bone tissue and regulate mineral deposition on bone surfaces. Osteoclasts degrade and resorb bone tissue. Osteocytes were formerly osteoblasts embedded in the bone matrix and communicate with other bone cells to regulate bone remodeling and respond to mechanical stresses on bones.
This document provides an overview of bone histology and development. It discusses that bone is a specialized mineralized connective tissue that can be divided into compact and cancellous bone microscopically. Bone develops through either endochondral or intramembranous ossification. The key cells involved are osteoblasts, which form new bone, and osteoclasts, which resorb bone. Bone is remodeled throughout life by the balanced actions of these cells.
Miacalcic Training 2004 Platform Syr April 03haithamo
The document provides information about MIACALCIC® Nasal Spray, a treatment for post-menopausal osteoporosis. It discusses the development and approval of the nasal spray formulation of calcitonin-salmon for this indication. It also provides background information on osteoporosis prevalence, risk factors, consequences such as fractures, and the role of bone remodeling and calcium homeostasis in the disease.
Bone is a specialized connective tissue composed of both organic and inorganic parts. The organic part includes collagen and other proteins, while the inorganic part contains calcium and phosphate minerals. Bone contains three main cell types - osteoprogenitor cells that develop into osteoblasts or osteoclasts. Osteoblasts form new bone by secreting proteins and minerals, osteoclasts break down bone, and osteocytes maintain bone structure. Together these cells regulate bone remodeling through signals that stimulate or inhibit each other's activity.
This document discusses the anatomy and structure of alveolar bone. It begins by classifying bone and describing its composition and functions. It then focuses on the specific properties of alveolar bone, including that it develops from the dental follicle and supports tooth roots. The key cellular and structural elements of alveolar bone are described, such as bone cells, bone matrix, Sharpey's fibers, and blood supply. In summary, the document provides an overview of the development, functions, cellular components, and vascular features of the specialized alveolar bone that surrounds and supports teeth.
Bone is a living tissue that provides structure and support. It can be classified based on shape, development, histology, and composition. The alveolar process forms with tooth development and eruption to support teeth in the jaw. It consists of cortical and cancellous bone layers surrounded by osteoblasts and osteoclasts, which build and resorb bone through various signaling pathways and enzymes.
This document provides an overview of bone formation, resorption, and remodeling. It discusses the classification of bones based on shape and development. It describes the composition of bone including cells like osteoblasts, osteoclasts, and osteocytes. Bone formation is mediated by growth factors while resorption involves acid secretion and enzyme activity by osteoclasts. Remodeling is a continuous process where old bone is replaced, maintaining bone strength through the coupled activities of formation and resorption. Markers of bone turnover provide information about these dynamic processes.
There are two main types of osteoporosis: primary and secondary. Primary osteoporosis is more common in post-menopausal women and affects those over 50, causing the loss of bone density as aging causes bone breakdown to outpace bone formation. Secondary osteoporosis is caused by an underlying health condition or medication that directly or indirectly decreases bone density and increases osteoporosis risk later in life.
The document discusses the development and structure of alveolar bone. It notes that alveolar bone develops from the dental follicle, where ectomesenchymal cells differentiate into osteoblasts that lay down bone matrix. Alveolar bone is composed of two parts: the alveolar bone proper that lines the tooth sockets, and the supporting bone below it. The alveolar bone proper appears as the lamina dura on radiographs and is resorbed during tooth movement. The supporting bone includes compact cortical plates and spongy cancellous bone between the plates and alveolar bone proper.
Marine VHF radio is used for rescue communication by vessels at sea. It operates between 156-162 MHz and uses frequency modulation. Newer models have additional features like digital selective calling and weather broadcasts. Selectivity is the ability to receive desired signals clearly when traffic is high. Higher selectivity is needed in busy areas and provided by fixed-mount versus handheld radios. Key considerations for marine VHF radios include weather resistance, performance in high traffic, and a provider with quality products.
Marine VHF radio is one such instrument that is in use for decades to avoid collision in sea and direct vessels in the right direction. These radios are used as an aid to keep you on the right track and call for aid when in distress. These radios operate on very high frequencies i.e. between 156 MHz to 162 MHz dedicated for marine communication. For further information about marine vhf radios visit: http://www.sailradios.com/Marine-Communication-VHF-Radios-s/1825.htm
Ship owners, managers, officers and crew need cost-effective communications that are simple to operate, easy to maintain and operate seamlessly around the world. That’s what Singtel Office At Sea offer. Our services and technology can bridge Inmarsat, Iridium, VSAT, WiFi and mobile access automatically to provide voice, Internet, email and high-value applications from weather data to ship management tools wherever the vessel travels.
The document provides guidance on proper radio voice procedure and techniques. It discusses considerations for talking on the air such as using voice procedure and proper technique. It emphasizes the importance of being brief, clear, and disciplined when communicating over radios. Standard words and phrases called prowords are defined that have special meanings to facilitate efficient radio communication. The phonetic alphabet is also described for clearly spelling words over the radio. Proper initiation of calls is outlined using standard call signs and prowords.
ACR Electronics will present complete and concise information on the various types of distress signaling devices
on the marine market today in support of the National Safe Boating Council’s “Saved by the Beacon” outreach and
education campaign promoting beacon use. Strategically mapping the distances in which VHF radio vs. satellite
phones vs. cell phones vs. 406 MHz beacon technology benefit’s start and stop.
As technology becomes more affordable and more efficient, it is important for boaters to understand what devices are best suited for their aquatic emergency action plans. An explanation on having the proper distress communications devices on board will benefit boaters, boating professionals and maritime safety advocates. It will also create a cohesive understanding of how these devices can assist in more efficient search and rescues. This will be defined with market breakdowns and statistical success for those who use the correct methods of technology.
Best practices on responsible ownership and proper maintenance of communication devices will conclude this
presentation.
Radar is used for collision avoidance, navigation, and pilotage. The radar screen displays range rings and a ship's head marker. International regulations require proper use of radar if fitted, including long-range scanning to obtain early warning of risk of collision and radar plotting. Assumptions should not be made based on limited radar information. Regulations also specify radar reflector size requirements. Collision avoidance using radar follows the rules to alter course depending on sector of detected vessels. Different radar display modes like head-up and north-up have benefits and drawbacks. Factors like range, target size and material, and false or interference echoes must be considered when using radar. Attending an RYA radar course is recommended prior to use.
William Ray Nelson Jr. has extensive experience working on vessels in the oilfield, towing, and offshore industries as a deckhand, assistant engineer, and captain. He holds numerous credentials including a 100 Ton Master license and experience on supply vessels, towing vessels, and crew boats. Nelson also has a background in automotive sales management and served in the US Navy.
Tides are the rising and falling of sea levels caused by the combined effects of the gravitational pull of the moon and the sun and the centrifugal force of the Earth's rotation. The moon has the strongest influence due to its closer proximity. This creates bulges in the ocean that result in two high tides and two low tides every 24 hours and 50 minutes. Spring tides occur at new and full moons when the sun, moon, and Earth are aligned, creating higher tides. Neap tides happen when the sun and moon are at right angles, resulting in smaller differences between high and low tides.
IALA Buoyage System and Visual Aids to NavigationLearnmarine
The document summarizes the International Association of Lighthouse Authorities (IALA) buoyage system and visual aids to navigation. The system provides six types of marks to indicate navigational features: lateral marks for channel edges, cardinal marks for hazards, isolated danger marks, safe water marks, special marks, and emergency wreck marking. Lateral marks are the only ones that differ between regions A and B. Region A uses red buoys with red tops for port sides and green buoys with green cone tops for starboard sides. Other types of marks include safe water marks with red and white stripes, special purpose yellow buoys, and emergency wreck marks with blue and yellow flashing lights.
The document discusses various navigational aids and chart symbols used in buoyage and chartwork including lateral markers to mark channels, contours to indicate depths, isolated dangers, safe water marks, emergency wreck marks, and special marks. It emphasizes that charts provide useful information about depths, hazards, rules and regulations, navigational aids, and other details to help map the sea for maritime navigation and safety.
The document provides an overview of key rules and definitions from the Navigation Rules for Marine Law Enforcement Officers. It defines terms like vessel, underway, power-driven and sailing vessels. It outlines lighting requirements and sound signals. It discusses rules for determining risk of collision, taking action to avoid collision, operating in narrow channels, overtaking situations, head-on encounters, and crossing situations.
1. Shapes used to identify vessels must meet certain size requirements and be black in color, including balls at least 0.6m in diameter, cones with 0.6m base diameters, and cylinders with 0.6m diameters and heights twice the diameter.
2. The vertical distance between shapes on a vessel must be at least 1.5m, though smaller shapes and distances are allowed on smaller vessels.
3. Various shapes indicate a vessel's status or activities, such as cones pointing up or down for sailing vessels, balls or diamonds for vessels not under command or restricted in maneuvering, and balls for vessels aground.
The document provides an overview of international and inland nautical rules of the road. It discusses key topics such as required navigation lights for vessels, sound signals, and right-of-way rules for different vessel encounter situations such as meeting, overtaking, and crossing. Specific lights, shapes, and whistle signals that vessels must use to identify themselves and communicate intentions are described.
This document provides a history of international conventions and regulations regarding maritime safety from 1914 to 2012. It summarizes key developments like the establishment of the International Convention for the Safety of Life at Sea after the Titanic disaster in 1914, the introduction of radar in the 1960s, and the requirement for Electronic Chart Display systems in 2012. The document also describes various life saving signals, distress communication methods, and emergency equipment used at sea like flares, dye markers, and radio protocols.
Marine communication refers to the exchange of information between vessels at sea or between vessels and shore stations. It has evolved from early flag signaling to modern radio technologies. Key developments include the early use of radio telegraphy using Morse code, integration of VHF radio with digital selective calling for ship-to-ship and ship-to-shore communication, establishment of satellite systems like INMARSAT for global coverage, and adoption of the Global Maritime Distress Safety System (GMDSS) to standardize radio equipment required on ships based on their area of operation. Modern marine communication systems aim to ensure vessels can reliably exchange information to aid navigation and quickly transmit distress signals.
VHF radio uses frequencies between 30-300 MHz for applications like radio, TV, and two-way communications over short distances. The document discusses VHF propagation characteristics and antennas before introducing the Icom VHF 5061 radio. It has modes for selective calling, emergency calls and ID transmission. Features include detachable front panel, wide frequency range, voice scrambler and enhanced scanning abilities. The radio is suitable for ground-to-air, public safety and business communications.
The document discusses the hierarchical structure and mechanical properties of bone. At the macrostructural level, bone is divided into cortical and cancellous bone based on their density. Cortical bone forms the hard outer shell, while cancellous bone is found at the interior and has an irregular structure. Cancellous bone remodels more frequently than cortical bone. Mechanical properties vary between cortical and cancellous bone as well as between different bones and regions within the same bone.
6. alveolar bone in health part b dr-ibrahim_shaikhDrIbrahim Shaikh
This document discusses the cells and components that make up healthy alveolar bone. It describes the main cell types, including osteoprogenitor cells that develop into osteoblasts or osteoclasts. Osteoblasts secrete osteoid and regulate mineralization, while osteoclasts are responsible for bone resorption. The bone matrix contains collagen fibers and hydroxyapatite crystals, along with noncollagenous proteins. Alveolar bone undergoes physiological remodeling through the coordinated actions of osteoblasts and osteoclasts, allowing adaptation to tooth movement and replacement over time.
Osteoblast and Osteoclast Crosstalks: From OAF to EphrinKarlFrank99
This document summarizes research on communication between osteoblasts and osteoclasts during bone remodeling. It discusses how osteoblasts recruit osteoclast precursors and regulate osteoclast differentiation through factors like RANKL and OPG. It also describes how osteoclasts may release growth factors like TGF-beta from resorbed bone to signal osteoblasts. More recently, ephrin and Eph receptors have been shown to mediate direct communication between osteoblasts and osteoclasts through cell-cell contact. Maintaining the balance of bone resorption and formation through these cellular interactions is essential for healthy bone remodeling.
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This document is a pathology assignment submitted by Rebira Workineh to their professor Dr. Jebessa Gemechu. It discusses several musculoskeletal pathologies in 3 sections - congenital disorders of bone and cartilage, metabolic bone diseases, and tumors of adipose tissue. Key topics summarized include osteogenesis imperfecta, achondroplasia, Paget's disease, osteoporosis, rickets, osteomalacia, osteonecrosis, and lipomas vs liposarcomas. The assignment provides details on pathogenesis, clinical features, diagnosis, and management of each condition.
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Bone is a type of connective tissue composed of cells and a mineralized organic matrix. There are three main types of bone cells - osteoblasts which form bone, osteocytes which maintain bone, and osteoclasts which resorb bone. Bones develop through two processes - endochondral ossification where cartilage is replaced by bone, and intramembranous ossification where bone forms directly from mesenchymal cells. Bone growth occurs through modeling which increases bone diameter, and remodeling which replaces old bone with new bone. Hormones like PTH and estrogen help regulate bone growth and remodeling throughout life.
Anatomy of bone, General orthopedics and fracture healingadityarana242502
Bone healing occurs in stages including hematoma formation, granulation tissue formation, callus formation, consolidation/remodeling. Callus formation provides structural integrity and is the first sign of healing seen on x-rays at 3 weeks. Consolidation/remodeling replaces the initial woven bone callus with stronger lamellar bone over 1-4 years. Factors like age, bone type, fracture pattern, and immobilization affect healing time, with children and cancellous bones healing faster and inadequate immobilization risking non-union.
Development of bone
Microstructure of bone
Composition of bone
Formation of osteoblasts
Mineralisation of bone
Formation of osteoclasts
Resorption of bone
Macrostructure of bone
Volume changes in bone
Bone healing
Improving Bone Health
Aging can take a toll on bone health, but with proper care and attention, bone health can be improved to lower the risk of painful conditions like osteoporosis. Some tips for better bone health include taking calcium supplements, quitting smoking, and considering a bone density test to understand bone health status and determine if medications may help. Speaking to chiropractors at Fick Chiropractic Centers can provide more information on improving bone health.
The Mechanisms of Treatments for OsteoporosisHeather Drew0519.docxcherry686017
The Mechanisms of Treatments for Osteoporosis
Heather Drew
05/19/12
The Mechanisms of Treatments for Osteoporosis
Heather Drew
05/19/12
Introduction
The cost of aging is one debt that we all share. Advances in the fields of healthcare and biomedical research have allowed us to extend our lives as much as is currently possible and yet we still battle with many age-related illnesses. Age is a major risk factor for detrimental morphological changes that the body undergoes as well as the onset of cancer or degenerative diseases (Kohlmeier, Lynn Kohlmeier, 1998). One set of collective physical markers that are indicative of the aging process, frailty, is characterized by the loss and dysfunction of skeletal bone and muscle (Lauretani F et al, 2003). Frailty not only increases the risk of both acute and chronic disease but is also a predictor of mortality. Osteoporosis itself is the manifestation of altered cellular senescence and other age-related factors and contributes greatly to frailty and increased risk of bone fracture. By studying the molecular mechanisms that dictate the cycle of bone formation and resorption, scientists have been able to identify novel methods that may used to counter frailty and ultimately osteoporosis.
Background
Osteoporosis is an age-related disease of the bone that is characterized by reduced bone mineral density, disruption of the microarchitecture of osseous tissue, and alterations in bone-related proteins (Raisz L, 2005). These changes lead to frailty of the bones and increase the risk of disease and mortality. Osteoporosis occurs when there is a disruption of bone tissue homeostasis, or, the balance between bone resorption and bone formation (Poole KE, Compston JE, 2006). As seen in Figure 1 and Figure 2, this balance largely depends on the development of osteoblasts and osteoclasts. Both cell types are derived from bone marrow progenitors; osteoblasts differentiating from mesenchymal lineage and osteoclasts from hematopoietic cells. The production of such progenitor cells has been shown to be regulated by cytokines (such as interleukin-6 and interleukin-11) as well as sex steroids (such as estrogen). This indicates that both inflammatory response as well as hormonal changes such as menopause may lead to an increased risk of osteoporosis (Raisz L, 2005). In regards to the affect of aging on this cycle, cellular senescence may decrease the ability of the bone marrow to form osteoblast precursors leading to a loss in bone formation and increase in fractures. The large amount and variety of regulatory factors that play key rolls in the homeostasis of bone formation has led to multiple drug targets and therapies that may possibly be able to combat the detrimental effects of osteoporosis.
Lining Cells
Osteoclasts
Osteoblasts
Osteocytes
Mononuclear Cells
Mesenchymal Stem Cells
Hematopoietic Stem Cells
Fig. 1. Schematic outline of the bone remodeling system. In the bone tissue, osteoclasts play a major role ...
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Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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For whom the bell tolls distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases
1. Bone 54 (2013) 272–278
Contents lists available at SciVerse ScienceDirect
Bone
journal homepage: www.elsevier.com/locate/bone
Mini-Review
For whom the bell tolls: Distress signals from long-lived osteocytes and the
pathogenesis of metabolic bone diseases
Stavros C. Manolagas ⁎, A. Michael Parfitt
Division of Endocrinology & Metabolism, Center for Osteoporosis & Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Central Arkansas Veterans Health Care System, Little Rock, AR 72205, USA
a r t i c l e
i n f o
Article history:
Received 11 July 2012
Revised 12 September 2012
Accepted 17 September 2012
Available online 23 September 2012
Edited by: Lynda F. Bonewald,
Mark E. Johnson, and Michaela Kneissel
Keywords:
Osteocytes
Apoptosis
Autophagy
Involutional osteoporosis
Post-menopausal osteoporosis
Steroid-induced osteoporosis
Osteogenesis imperfecta
Anti-resorptive therapies
a b s t r a c t
Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured
within the lacunar–canalicular system and mineralized matrix, osteocytes are ideally located throughout
the bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently
controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence
indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the
pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyteoriginated signals may also contribute to the increased bone fragility associated with bone matrix disorders
like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab.
This article is part of a Special Issue entitled "The Osteocyte".
Published by Elsevier Inc.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Involutional osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contribution of osteocyte death to increased bone fragility with old age . . . . . .
Osteocytes and cortical porosity . . . . . . . . . . . . . . . . . . . . . . . . .
Failure of osteocyte autophagy with age . . . . . . . . . . . . . . . . . . . . .
Post-menopausal osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . .
Glucocorticoid-induced osteoporosis . . . . . . . . . . . . . . . . . . . . . . .
Immobilization-induced osteoporosis . . . . . . . . . . . . . . . . . . . . . .
A role of osteocytes in diseases of abnormal bone matrix . . . . . . . . . . . . .
Above baseline reversal of bone turnover following discontinuation of antiresorptive
Concluding thoughts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
“No man is an island, entire of itself; every man is a piece of the continent, a part of the main; if a clod bee washed away by the sea,
⁎ Corresponding author at: Division of Endocrinology and Metabolism, 4301 W.
Markham St., Slot 587, Little Rock, AR 72205-7199, USA.
E-mail address: manolagasstavros@uams.edu (S.C. Manolagas).
8756-3282/$ – see front matter. Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.bone.2012.09.017
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272
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Europe is the less, as well as if a promontory were, as well as if a manor
of thy friends or of thine own were; any man's death diminishes me,
because I am involved in mankind. And therefore never send to know
for whom the bell tolls; it tolls for thee.” John Donne, Devotions upon
Emergent Occasions, Meditation XVII, 1624.
Osteocytes are by far the more abundant cell type in bone: one
thousand times more than osteoclasts and ten times more than
2. S.C. Manolagas, A.M. Parfitt / Bone 54 (2013) 272–278
osteoblasts [1]. In difference to these other two cell types which are
short-lived and only transiently present on a small fraction of the
bone surface, osteocytes are long-lived and deployed throughout the
skeleton. In many regions of the skeleton, osteocytes persist until
the bone in which they lie is resorbed, so that their lifespan is the
same as that of bone. Because of their long lifespan, osteocytes are
subjected to the adverse effects of the aging process and therefore
are directly relevant to pathophysiology of the aging of the skeleton.
In a manner analogous to neuronal cells, osteocytes form an elaborate communication network with each other, endothelial cells of the
bone vasculature, and cells of the bone surface and the marrow, via
cytoplasmic process and gap junctions [2]. Because of these unique
features, osteocytes are ideally suited to mediate the homeostatic
adaptation of bone to mechanical forces. Detection of changes in strain
by osteocytes leads to changes in osteoclast and/or osteoblast recruitment by mechanisms which are slowly emerging, that counteract the
change in strain. Indeed, it is abundantly clear by now that osteocytes
not only detect the need for bone regeneration, but they also choreograph the regeneration process by independently controlling the rate
limiting steps of bone resorption and formation [3] (Fig. 1).
Osteocytes, but not osteoblasts or their precursors, are the essential cellular sources of RANKL for osteoclast formation [4,5]. This
particular distinction is important since osteocytes are downstream
from bone formation and therefore RANKL expression in this cell
type cannot explain the coupling of bone formation to bone resorption. Presently, it remains unclear how osteocyte-derived RANKL
reaches osteoclast progenitors to activate its receptor RANK. However, RANKL is produced as a membrane protein that can be shed to
form a soluble form, sRANKL [6]. Therefore, osteocytes may control
osteoclast formation via the release of sRANKL into the lacunar–
canalicular system, which directly communicates with the bone marrow. A similar process is probably involved in the regulation of bone
formation by osteocytes through the secretion of sclerostin and perhaps Dkk1 [7,8]. An alternative possibility is that RANKL, attached to
the membranes of dendritic osteocyte processes extending onto the
bone surface, interacts directly with osteoclast progenitors.
In this brief review, we will summarize emerging evidence that
signals arising from apoptotic and old/or dysfunctional osteocytes
are important participants in the pathogenesis of the most common
forms of osteoporosis. In addition we will discuss the possibility that
pOC
pOB
RANKL
OCs
Sclerostin
OBs
Osteocytes
?
Fig. 1. Model depicting mechanisms by which osteocytes may independently control
bone resorption and bone formation. Osteoclasts (OCs) and osteoblasts (OBs) within
a cancellous bone BMU are shown as being derived from precursors (pOC and pOB).
Osteocytes alter the rate of bone remodeling by controlling osteoclast formation via
production of RANKL. Osteocytes also control the balance between formation and
resorption by regulating osteoblast formation via production of sclerostin.
Reproduced from Jinhu Xiong and Charles A. O'Brien J Bone Miner Res. 2012; 27:499–505.
273
osteocyte-derived signals may also contribute to the increased bone
fragility associated with congenital matrix disorders like osteogenesis
imperfecta, and perhaps the reversal of bone turnover following discontinuation of anti-resorptive therapies.
Involutional osteoporosis
Decreased bone mass is only one of many age-related mechanisms
responsible for the increase of fracture risk in the elderly [1,9].
Indeed, the risk of hip fracture between the ages of 50 and 80 years
increases 30-fold [9,10], but only a 4-fold increase can be accounted
by the decline in BMD [11]. Age-related changes in the bone itself clearly
contribute to the increase in fracture risk independently of BMD.
In many areas of the skeleton osteocytes survive until the bone in
which they lie is resorbed, so that their lifespan is the same as the age
of that bone. In areas of very low turnover, osteocytes may die by apoptosis, leaving lacunae which appear empty in histologic sections [12],
but which may contain the remnants of osteocytes which have not
undergone phagocytosis [13], but are lost during section preparation.
Almost fifty years ago, Harold Frost was the first to conceive that the
lifespan of osteocytes is relevant to the pathophysiology of osteoporosis
[14]. He noted that osteocyte death in rib cortical bone, inferred from
the presence of an empty lacuna, increased in prevalence with age
and was followed by hypermineralization of perilacunar bone and
later by filling of canaliculae with mineralized connective tissue. Such
changes are collectively referred to as micropetrosis and probably lead
to increased brittleness of bone [15]. From these and other data Frost
estimated the natural lifespan of osteocytes at about 25 years [16]. It
is generally believed that only in cortical bone would osteocytes be
left undisturbed by remodeling long enough for this intrinsic lifespan
to be exceeded, but this view disregards the effect of distance from
the surface on the probability of remodeling, and hence mean bone
age [17]. In human cancellous bone, this effect is minor in bone less
than 50 μm from the surface, but as the depth increases this effect increases rapidly, so that bone more than 75 μm from the surface is essentially isolated from surface remodeling and will be at least as old as the
years of age of the subject since skeletal maturity; since during growth
trabeculae increase in thickness by remodeling with positive balance,
the age of such bone could be even greater [18].
Even in normal human iliac cancellous bone, a substantial proportion is more than 20 years old [17] so it is not surprising that osteocyte
death (inferred from an empty lacuna) has been demonstrated. In
superficial bone (b25 μm from the surface) obtained from healthy
women the density (number/unit area) of total lacunae, osteocytes
and empty lacunae does not change with age because bone in which
some osteocytes have died is replaced by bone containing a full complement of osteocytes [12]. The data suggest that rather than having a fixed
lifespan, osteocytes die by a stochastic process occurring at a fractional
rate of about 2.5%/year. Consequently, in deep bone (more than 45 μm
from the surface) that is rarely or never remodeled, osteocyte density
declines exponentially with age, approaching an asymptotic value
which at age 75 is about 40% of the value at age 20 [19]. Evidently osteocyte death is dependent on the age of the bone, not on the age of the
subject. In deep bone total lacunar density is lower than in superficial
bone and falls substantially with age, so that micropetrosis, the only
process that could lead to obliteration of lacunae, occurs in cancellous
as well as in cortical bone [12]. There is a close spatial relationship
between empty lacunae and microscopic fatigue damage [20] but it
is unclear which occurs first, although both are the expected consequences of excessive bone age [21].
Contribution of osteocyte death to increased bone fragility with
old age
The age related decline in osteocyte number is accompanied by
reduced bone strength, both in patients with vertebral fracture [22]
3. 274
S.C. Manolagas, A.M. Parfitt / Bone 54 (2013) 272–278
and in healthy mice [23]. Notably, ablation of osteocytes in young
mice recapitulates at least some of the effects of old age on bone
and rapidly leads to decreased bone strength, microfractures, and
osteoporosis [24]. Several mechanisms likely contribute to this relationship, and increased release of RANKL triggered by the death of
osteocytes may be one of them. Consistent with this, reduced osteocyte density in central cancellous bone is associated with increased
surface remodeling [19], which is an independent contributor to
bone fragility [25]. Additionally, osteocyte death with advancing
age leads to a decline in bone vascularity and hydration, which reduces bone strength by mechanisms not yet fully understood, but
which probably include changes in crystallinity and promotion of
micropetrosis [15,26]. Conversely, protection of osteocytes from
the adverse affect of aging on their apoptosis in the mouse maintains bone crystallinity, vasculature volume, circulation of interstitial fluid, and strength [26].
Osteocytes and cortical porosity
The term osteoporosis, coined by the French pathologist Jean
Georges Chretien Frederic Martin Lobstein ‘the Younger’ (1777–1835),
is derived from the Greek words osteo (bone) and poros (little hole),
referring to the cavities which were observed by the pathologist in
certain patients' bones [27]. An increase in cortical porosity with age
was first noted in histologic studies reported by Amprino and Bairati
in 1936 in an Italian publication, and radiologically by Meema in 1969
[28]. One of the authors of the present article (MP) was the first to
explicitly identify increased cortical porosity as another factor in bone
fragility [29]. He noted the similarity of bone fragility occurring during
the high turnover of the adolescent growth spurt and early postmenopause. This argument was further developed in a later paper
[30]. Until recently, the contribution of cortical porosity to the decreased bone strength and increased fragility had been underappreciated because of technical limitations for its detection. All these years,
much more attention was placed instead on the more readily measurable bone mineral density (BMD). It was not until the recent development of high resolution peripheral CT that it was shown for the first
time that cortical porosity may be responsible for a substantial amount
of the loss of bone and the resultant structural deterioration that occurs
after the age of 65 [31,32].
Recent studies from the laboratory of Robert Jilka have provided
genetic evidence for a cause-and-effect relationship between the
apoptosis of osteocytes and cortical porosity [33]. In this work, the
investigators used mice that are deficient for both Bak and Bax, two
genes indispensable for apoptosis, selectively in osteoblasts and osteocytes. In two different models (one using an osteocalcin Cre deleter,
and the other using an osterix Cre deleter), there was a substantial increase in trabecular bone mass that was maintained up to 22 months
of age. This finding provides the first genetic demonstration that
attenuation of osteoblast apoptosis can indeed increase the working
lifespan of this cell type and lead to bone anabolism — a concept
suggested by several earlier studies [34,35]. Unexpectedly, however,
the Bak/Bax-deficient mice also exhibited a 7-fold increase in pore
formation throughout the femoral cortex by 22 months of age, increased expression of RANKL and numerous osteoclasts within the
pores. Notably, at the same age, cortical porosity in the wild type
controls was limited to the distal metaphysis. More strikingly, in
both Bak/Bax-deficient and wild type mice, the pores were adjacent
to dysmorphic osteocytes, the number of which was far greater in
the Bak/Bax-deficient mice. These findings demonstrate that abrogation of apoptosis prolongs the working lifespan of short-lived osteoblasts, but it exaggerates the adverse effects of aging on long-lived
cortical osteocytes. Moreover, they strongly suggest that distress signals from age-damaged osteocytes and a focal increase of RANKL production are the likely culprits of cortical porosity.
Failure of osteocyte autophagy with age
“Autophagy”, the Greek word for self-eating, is a highly conserved
process that is mediated by lysosomes and is critical for cellular
defense against stressful stimuli. Autophagy is particularly important
for terminally differentiated long-lived cells, such as osteocytes, in
which damaged components are not diluted by cell replication and
need to be eliminated before becoming toxic. During autophagy,
large structures such as organelles (i.e. mitochondria) and unwanted
or damaged proteins are recycled. During periods of starvation,
autophagy provides amino acids that are essential for survival. Autophagy is stimulated by numerous stressors including oxidative
stress, impaired mitochondria function, hypoxia, as well as caloric restriction [36–38]. Autophagy prevents diseases. Failure of autophagy
(i.e. the inability to mount an autophagic response), on the other
hand, is responsible for the ultimate demise of long-lived, postmitotic cells in many organs, including the brain, heart, muscle, and
kidney. Indeed, autophagy failure is linked to degenerative diseases
of the nervous system, like Alzheimer's and Parkinson's disease, as
well as heart failure and cancer [39].
Failure of osteocyte autophagy, resulting from long-term increase
in oxidative stress, may be yet another age-related mechanism contributing to the pathogenesis of involutional osteoporosis. Indeed,
a compromised autophagic response by osteocytes and the resulting
apoptosis could well be the trigger of pathologic remodeling and
the increased cortical porosity associated with old age. It was recently
shown in vitro that osteocyte autophagy increases in response to
stresses, such as growth factor starvation, hypoxia, and glucocorticoids
[40]; and that increased autophagy plays a protective role against
glucocorticoid-induced cell death [41]. In addition, unpublished work
from Dr. O'Brien's laboratory in our group has revealed that expression
of autophagy-related genes is lower in the cortical bone of 20-monthold, compared with 6-month-old, mice [40]. This is associated with an
increase in the amount of mitochondrial DNA, which is a consequence
of reduced turnover of mitochondria. To directly address whether
autophagy is functionally important in osteocytes, O'Brien and colleagues went on to delete ATG7, a gene that is essential for autophagy,
from osteocytes using the DMP1-Cre transgene, which is active predominantly in osteocytes. Similar to the results from aged mice, the
reduction in autophagy in the conditional KO mice was associated
with an increase in the levels of mitochondrial DNA isolated from cortical bone. Moreover, BMD was significantly lower, compared to littermate controls, in the spines and femurs of both male and female
conditional KO mice beginning at 4 months of age and continuing to
at least 6 months of age without differences in body weight between
genotypes. Micro-CT analysis revealed low cancellous bone volume,
low cortical thickness, and high cortical porosity in 6-month-old conditional KO mice compared with control littermates. At this age, osteoclast
number, osteoblast number, bone formation rate, and wall width were
also lower in the conditional KO mice. In addition, oxidative stress was
higher in the bones of conditional KO mice as measured by reactive
oxygen species levels in the bone marrow of the femur and by p66shc
phosphorylation in vertebral bone. Strikingly, all these changes including this low bone mass and low rate of bone turnover are similar to
those observed in aged wild type mice. Hence, these results demonstrate that loss of autophagy in osteocytes leads to low bone mass associated with low bone remodeling and suggest that a decline in osteocyte
autophagy with age contributes to the low bone mass associated with
aging.
Post-menopausal osteoporosis
The decline of estrogen production at menopause leads to loss
of bone that is associated with an increase in the bone remodeling
rate, increased osteoclast and osteoblast numbers, and increased resorption and formation, albeit unbalanced. Conversely, estrogen replacement
4. S.C. Manolagas, A.M. Parfitt / Bone 54 (2013) 272–278
decreases bone resorption, restrains the rate of bone remodeling, and
helps to maintain a focal balance between bone formation and resorption. These effects result from influences on the birth rate and lifespan
of osteoclast and osteoblast lineage cells that are mediated via direct
actions of estrogens on these two cell types as well as indirect actions
mediated via cytokines produced by osteocytes, osteoblastic/marrow
stromal cells, and perhaps T and B lymphocytes, macrophages, and dendritic cells [42–44].
Consistent with evidence for a direct anti-apoptotic effect of estrogens on osteocytes [45,46], estrogen deficiency increases the prevalence of osteocyte apoptosis in both cancellous and cortical bone in
animals and humans [47–49]. Importantly, in a recent study in mice,
the increased osteocyte apoptosis caused by loss of estrogens was
regional, rather than uniform, in the bone cortex; and the location
of the apoptotic osteocytes was tightly correlated with the areas
where endocortical resorption was subsequently activated [50]. This
observation is in line with the idea that apoptotic osteocytes, or
more likely the live neighbors of the dead cells, produce factors that
increase osteoclast formation and recruitment in their vicinity, leading to the resorption and thereby removal of the dead cells. These
latest findings together with the demonstration of the essential role
of osteocyte-derived RANKL in osteoclastogenesis and bone remodeling, also support the long-held view that at least some remodeling is
a targeted, as opposed to stochastic, process in which cells that can
sense mechanical damage and/or the death of their neighbors are
beacons for the excavation and repair of a specified area of bone
and the removal of the dead cells [3].
Glucocorticoid-induced osteoporosis
Glucocorticoid excess, similar to the osteoporosis of old age, decreases bone strength disproportionately to its adverse effect on bone
mass; and frequently presents with fractures as early as three months
following the initiation of therapy with these agents and before any
detectable decline on bone mass [51]. Extensive evidence implicates
an increase in the prevalence of osteocyte apoptosis in the rapid
increase of fracture incidence in patients with this condition [52].
Glucocorticoids strongly and rapidly stimulate osteoblast and
osteocyte apoptosis directly, and also suppress osteoblastogenesis
while increasing the lifespan of osteoclasts [13,53–55]. Glucocorticoids, like loss of mechanical strain, increase osteocyte apoptosis by
interfering with focal adhesion kinase-mediated survival signals,
thereby leading to anoikis [56]. Endogenous glucocorticoid production and sensitivity to the effects of glucocorticoids increase with
age, apparently contributing to the effects of old age in the development of osteoporosis. Increased sensitivity to glucocorticoids is the
result of increased bone expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, the enzyme that activates glucocorticoids. In both aging and pharmacologic hyperglucocorticoidism,
increased apoptosis of osteocytes can account for the loss of bone
strength that occurs before the loss of bone mineral density and the
mismatch between bone mineral density and the risk of fracture in
patients with glucocorticoid-induced osteoporosis [26,57,58]. Specifically, and similar to aging, in glucocorticoid excess the volume of the
bone vasculature and solute transport from the peripheral circulation
to the lacunar–canalicular system is decreased, leading to decreased
skeletal hydration [26]. The molecular underpinning of these effects
is decreased angiogenesis resulting from decreased VEGF production
by osteoblasts/osteocytes, as well as decreased VEGF action. These
changes represent a chain of interconnected pathogenetic mechanisms as indicated by anatomical evidence that the cellular processes
of osteocytes are in direct contact with the bone vasculature. Together with evidence that dehydration of bone decreases strength,
these new insights reveal that endogenous glucocorticoids increase
skeletal fragility in old age as a result of cell autonomous effects on
275
osteocytes leading to interconnected decrements in bone angiogenesis, vasculature volume, and osteocyte-lacunar–canalicular fluid.
Immobilization-induced osteoporosis
The mechanostat function of the osteocyte is dependent on interaction with the ECM. Osteocytes interact with the extracellular matrix
(ECM) in the pericellular space through discrete sites in their membranes, which are enriched in integrins and vinculin [59,60], as well
as through transverse elements that tether osteocytes to the canalicular wall [61]. Fluid movement in the canaliculi resulting from mechanical loading might induce ECM deformation, shear stress, and/
or tension in the tethering elements. The resulting changes in circumferential strain in osteocyte membranes might be converted into
intracellular signals by integrin clustering and integrin interactions
with cytoskeletal and catalytic proteins at focal adhesions [62,63].
Mechanical forces transduce signals through integrins and a signalsome
comprising actin filaments, microtubules, the focal adhesion kinase
FAK, and Src kinases, resulting in activation of the ERK pathway and
attenuation of osteocyte apoptosis [64]. Similarly, physiological levels
of mechanical strain imparted by pulsatile fluid flow prevent apoptosis
of cultured osteocytes [65].
Conversely, reduced mechanical forces increase the prevalence of
osteocyte apoptosis [66]. Within 3 days of tail suspension, mice or
rats exhibit an increased incidence of osteocyte apoptosis in both
trabecular and cortical bone. This change is followed 2 weeks later
by increased osteoclast numbers and cortical porosity, reduced trabecular and cortical widths, and decreased spinal bone mineral density
and vertebral strength. Importantly, whereas in ambulatory animals apoptotic osteocytes are randomly distributed, in the unloaded rodents
apoptotic osteocytes are preferentially sequestered in endosteal cortical
bone, the site that is subsequently resorbed. Moreover, treatment with
an apoptosis inhibitor blocks both the unloading-induced apoptosis and
the increased intracortical resorption [67]. The effect of unloading on
osteocyte apoptosis and bone resorption is reproduced in transgenic
mice in which osteocytes are refractory to glucocorticoid action, indicating that stress and hypercortisolemia cannot account for these effects [66]. Hence, diminished mechanical forces eliminate signals that
maintain osteocyte viability, thereby leading to apoptosis. Intriguingly,
a ligand-independent function of the estrogen receptor is indispensable
for mechanically-induced ERK activation and attenuation of osteocyte
apoptosis [68], consistent with reports that mice lacking the estrogen
receptors α and β exhibit poor osteogenic response to loading [69].
The mechanism(s) by which reduced mechanical forces trigger
osteocyte apoptosis remain unclear, but a decrease in nitric oxide
(NO) and prostaglandins is most likely involved [70]. In support
of this view, mechanical stimulation increases the production of NO
by osteocytes [71–73]. Mechanical stimulation of chicken and canine
bone also increases the production of prostaglandin E2 (PGE2) [74,75],
an agent with known antiapoptotic properties [76].
A role of osteocytes in diseases of abnormal bone matrix
Signals for osteocyte survival must also be provided by the ECM
itself. In agreement with this view, loss of survival signals from the
ECM causes osteoblastic cell apoptosis or “anoikis”, and neutralizing
antibodies to the ECM protein fibronectin induce osteoblast apoptosis
[77]. In addition, transgenic mice expressing collagenase-resistant
collagen type-I exhibit a striking increase in the prevalence of osteocyte and osteoblast apoptosis [78]. Collectively, these lines of evidence suggest that exposure of cryptic sites of ECM proteins by
matrix metalloproteinases is required for the maintenance of cell–
ECM interactions that result in “outside-in” integrin signaling that
preserves osteocyte viability. This scenario is consistent with in
vitro evidence that physiological levels of mechanical strain promote
survival of osteocytes via an integrin-mediated mechanism [64]. In
5. 276
S.C. Manolagas, A.M. Parfitt / Bone 54 (2013) 272–278
view of this, it is reasonable to suspect that osteocytes residing in the
bone of patients with matrix abnormalities sense the defective matrix
and generate signals to repair it, futile as this response may be. One
such condition may well be osteogenesis imperfect (OI).
OI is a genetic disorder characterized by increased bone fragility
and low bone mass. Although mutations affecting collagen type I are
responsible for the disease in most patients, the mechanisms by
which the genetic defects cause abnormal bone development have not
been well characterized. One possibility is that abnormal ECM leads
to misperception of strain by osteocytes such that the mechanostat
setpoint is too high [79]. Nevertheless, quantitative static and dynamic
histomorphometric analyses of tetracycline-labeled iliac bone biopsies
from children with OI types I, III, and IV revealed that surface-based
parameters of bone remodeling are increased in all OI types, indicating
increased recruitment of remodeling units [80]. Consistent with this,
the thickening of secondary trabeculae by remodeling is severely
compromised. Also long bones are narrower because periosteal apposition is reduced.
Above baseline reversal of bone turnover following
discontinuation of antiresorptive treatments
Commonly used drugs for the treatment of osteoporosis are
anti-resorptive agents that slow remodeling in proportion to their
anti-resorptive efficacy. The emergence of serious side effects with
the long term use of such agents, however, has raised major concerns
about the optimal duration of such therapies and their long term
consequences [81–83]. Moreover, in all instances, their effects are
transient and in the case of the newer and more effective ones, have
in fact a rapid resolution-of-effect with the potential for increasing
fracture risk [84]. Considering the preceding discussion it is inexorable that if necessary remodeling is postponed, microdamage and osteocyte death or dysfunction will accumulate, so that a period of catch‐
up is required to restore microdamage burden to normal.
Concluding thoughts
In keeping with the literary analogy, considerable evidence indicates that the bell tolls for dead or dysfunctional osteocytes, alerting
the rest of the osteocyte network to the need for removal of the
dead cell bodies and/or the repair of the damaged matrix (Fig. 2).
Removal of dead osteocytes by osteoclastic resorption is the only
option for cells that are entombed within mineral and are therefore
inaccessible to phagocytosis by ordinary macrophages. The molecular
means by which dead or unhealthy osteocytes convey their distress
signals to their alive, healthy neighbors remain completely unknown, but efforts to uncover them seem to us a very fruitful area
of inquiry. Mechanical loading stimulates Wnt signaling and thereby
osteoblastogenesis and bone formation in healthy bone, by decreasing
the production of the osteocyte-derived Wnt antagonist sclerostin
[85–87]. At this stage, it is unclear whether osteocyte death or dysfunction also leads to sclerostin-dependent changes in osteoblastogenesis
and bone formation, but reports of changes in the circulating levels
of serum sclerostin in some disease states have raised this possibility
[88]. Nonetheless, a lot more mechanistic studies and vigorous validation of the sclerostin assays and the biological relevance of circulating
sclerostin to bone metabolism, if any, are needed before firm conclusions can be drawn about the putative contribution of dead or dysfunctional osteocytes to compromised bone formation in pathologic states
[89]. Albeit, the evidence that dysapoptotic osteocytes (i.e. osteocytes
unable to undergo apoptosis because of the lack of Bak and Bax) cause
cortical porosity and lack of osteocyte autophagy recapitulates the low
bone turnover phenotype of old age in the murine skeleton suggests
that such efforts will be worthwhile [33,40].
Acknowledgments
SCM's research is supported by the National Institutes of Health
(P01 AG13918); the Department of Veterans Affairs (Merit Review);
and Tobacco Settlement funds provided by the University of Arkansas
RANKL
Distress Signals
Fig. 2. Illustration of the concept that the neighbors of apoptotic osteocytes (caused by microcracks in the particular instance depicted in the model) receive and propagate distress
signals (red arrow) that trigger the process of the removal of dead osteocytes and the abnormal matrix that surrounds them. Red arrows connecting osteocytes imply that such
signals travel through the lacunocanalicular system to reach the bone surface and thereby target the area in need of damage repair. RANKL is shown as a representative of probably
several additional mediators of the repair process.
Modified from Seeman, E. and Delmas, D.P. NEJM 2006; 354:2250–2261.
6. S.C. Manolagas, A.M. Parfitt / Bone 54 (2013) 272–278
for Medical Sciences. The authors wish to thank Leah Elrod for assistance in the preparation of the manuscript.
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