Bone Advanced


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Bone Advanced

  1. 1. PART I The Skeleton human mouse 206 bones > 200 bones 1
  2. 2. Bones can differ dramatically in their size and shape Bones of the inner ear Human femur What is bone? • Specialized form of connective tissue: mineralized collagen matrix, therefore very rigid and strong while still retaining some degree of flexibility • Other types of connective tissue: - Cartilage: semi-rigid form, glycoprotein rich - Ligaments: flexible bands, rich in collagen fibers, contribute to stability of the joint - Tendons: strong flexible bands, rich in collagen fibers, connect muscles with bone 2
  3. 3. Diverse functions of bone • Support • Protection (Skull) • Mineral storage (e.g. calcium homeostasis) • Hematopoiesis (bone marrow - postnatal) • Locomotion - muscular-skeletal system • Hearing Mechanisms of bone formation • Membranous ossification intramembranous bones: flat bones of the skull, clavicle, periosteum how: direct differentiation of cells within mesenchymal condensations into bone forming cells (osteoblasts) • Endochondral ossification endochondral bones:axial and appendicular skeleton, some bones in the skull how: replacement of a cartilagenous template by bone 3
  4. 4. Membranous bone formation osteoid compact bone Hartmann, TCB, 2006 Endochondral Ossification Hartmann, TCB, 2006 4
  5. 5. Different types of bone cells involved in bone homeostasis • osteoblasts bone forming cells • osteocytes terminal differentiated osteoblast • osteoclasts bone resorbing cells How do these cells look? Osteoblast mononucleated positive for AP (AP= alkaline phosphatase) Osteocyte mononucleated trapped within lacunae serve as mechanosensors Osteoclast multinucleated positive for TRAP (TRAP = tatrate-resistent alkaline phosphatase) 5
  6. 6. Origin of bone cells • osteoblasts: mesenchymal e.g. the first ob differentiate within the periosteum and form the bone collar postnatal: bone marrow • osteocytes: mesenchymal, terminal differentiated osteoblasts • osteoclasts: hematopoietic lineage; bone marrow Postnatal bone cell differentiation Hartmann, 2006 Encyclopedic Ref. 6
  7. 7. Bone architecture changes with age Vertebral body of Vertebral body of a young person an ederly person Outside factors affecting bone mass • Exercise: muscle contractions stimulate osteoblast function - increased production of bone peak bone mass reached at the age of 30 • Body weight: obesity can protect from osteoporotic bone loss • Diet affects bone: minerals and vitamins • Menopause in women: decrease in hormone level can lead to osteoporosis (treatment: HRT) 7
  8. 8. Terminology of changes in bone • osteopenia: decreased calcification or density of bone • osteoporosis: progressive reduction in quantity of bone • osteopetrosis: excessive formation of dense trabecular bone • osteosclerosis: abnormal hardening or eburnation of bone • osteohypertrophy: overgrowth of bone • osteosarcoma: tumor of the bone • osteochondrodysplasia: extreme bending of long bones • osteochondroma (exostosis): benign cartilaginous neoplasma • osteoblastoma: benign tumor of osteoblasts Changes in bones (associated with bone cells) • osteopenia: osteoporosis: osteopetrosis: (mild) (severe) wt wt wt Cause: osteoblasts are Cause: osteoblasts are not Cause: osteoclast deficiency not active enough active enough or no active OC and/or osteoclasts are too active 8
  9. 9. Congenital bone disorders • Achondroplasia • Osteogenesis • Marfan syndrome • Osteochondro- (Fgfr3 act. mutations) Imperfecta (skeletal overgrowth, matosis Dwarfism (brittle bones; lengthening of long bones prenatal form of osteoporosis) mutations in Fibrillin gene) (multiple exostoses) Skeleton formation begins during embryogenesis 9
  10. 10. Cartilage Types of cartilage (avascular tissue): • hyaline cartilage: • fibro-cartilage: • elastic cartilage: (e.g. trachea, nose, (e.g. intervertebral disc) (e.g. ext. ear, epiglottis) articular ends of bones, embryonic skeleton) The skeleton is derived from three different compartments Craniofacial skeleton Appendicular skeleton Axial skeleton Neural crest Somite Neural tube Lateral plate mesoderm Intermediate mesoderm Notochord Dorsal Medial Lateral Ventral 10
  11. 11. Different origins of membranous bone in the mouse skull pariental frontal nasal IP Cranial neural crest mesoderm According to: Jiang et al. 2002 Axial skeleton Origin: somites young somite intermediate somite differentiated somite 11
  12. 12. Limb skeleton Origin: lateral plate Condensing cartilage mesoderm anlagen in the limb Sclerotome Dermomyotome Starting to be distinguishable around day 4 in chick and day 11 in mouse Formation of the cartilagenous template in the limb naive signals initiating condensation & lineage cartilage template mesenchyme condensation lineage specification commitment & differentiation growth pre-chondroblast chondroblast chondrocyte perichodrial cell 12
  13. 13. Growth of the cartilage template Two mechanisms: • Appositional growth: new cartilage is added on the surface by recruiting chondroblasts from the inner layer of the perichondrium • Interstitial growth: new cartilage is formed within the cartilagenous template by chondrocytes dividing and producing additional matrix After initiation and formation of the cartilage template chondrocytes within the template undergo a controlled maturation program 13
  14. 14. Mitotically active postmitotic flattened Pre- proliferating hypertrophic hypertrophic Round proliferating chondrocytes chondrocytes chondrocytes chondrocytes PC: proliferative chondrocytes PHC: pre-hypertrophic chondrocytes HTC: hypertrophic chondrocytes MHTC: mature hypertrophic Bone collar chondrocytes periosteum transforming region PC PHC HTC MHTC Cilia are found on chondrocytes (uni-ciliated) Possible functions: •“Anker” for oriented secretion of extracellular matrix • Mechanosensor • Signaling center, as some receptors have been shown to localize to the cilium (for example smoothened the receptor required for transmitting the hedgehog signal) 14
  15. 15. Continuous growth of skeletal element is ensured by the growth plate Blood vessel invasion The Growth Plate round, proliferating chondrocytes flattened, stacked proliferating chondrocytes prehypertrophic hypertrophic β1 integrin -/- Wt transformation zone - defective cytokinesis osteogenic front - decreased proliferation - decreased cell adhesion - increased apoptosis newly formed bone 15
  16. 16. Integrin-(outside-in) signaling Replacement of cartilage by bone Blood vessel invasion 16
  17. 17. Histology of a juvenile long bone articular cartilage secondary ossification epiphysis center growth plate epiphysis primary spongiosa trabecular bone endosteum secondary spongiosa periosteum cortical bone bone marrow periosteum endosteum cortical bone Replacement of HTC by Bone Changes happening in the transformation zone: • Mineralization of cartilage matrix • Apoptosis of hypertropic chondrocytes • Phagocytosis of old cartilage matrix by osteo/chrondroclasts • Metalloproteases • Invasion of vascular system 17
  18. 18. Segmentation of the skeleton Skeletal elements are separated from each other by so-called joints Different types of joints (arthrosis): • synovial joints (diarthrosis): has a joint cavity that is enclosed by a fibrous capsule, which is lined by the synovial membrane. e.g. joints separating skeletal elements in limbs - free movement! • Non-synovial joints (synarthroses): • fibrous joints: skeletal elements are directly linked by fibrous tissue e.g. sutures between the skull bone - don’t allow movement! • cartilaginous joints: two skeletal elements are linked by cartilage e.g. joints between vertebral bodies - limited movement! Patterning of appendicular skeleton during embryonic development Alcian blue stained chicken hindlimbs Sequential process, proceeds from proximal to distal 18
  19. 19. The skeletal elements of the limb form by a process of branching and segmentation prechondrogenic (Sox9+, Col2a1+) chondrogenic (Sox9++, Col2a1++) joint (Sox9- , Col2a1- ) Development of the synovial joint by apoptosis Modified after P. Francis-West 19
  20. 20. Adult mouse knee joint Secondary ossification center meniscus Joint cavity bursa Articular cartilage Ligament cruciatum synovium subchondral bone Growth plate Ligaments of tibia of joint capsule Pathological changes of the joints • arthrosis: general term for degenerative affection of a joint • rheumatoid arthritis: systemic disease affecting connective tissue of joint, accompanied by inflammation and erosion of cartilage and bone due to synovial overgrowth • osteoarthritis: destruction of joints due to erosions of articular cartilage, accompanied by inflammation, eburnation of subchondral bone • gout: inflammation of the joint • synovitis: inflammation of synovial membrane • bursitis: inflammation of bursa (german: Schleimbeutel) 20
  21. 21. Histological changes in RA and OA Rheumatoid arthritis (RA) Osteoarthritis (OA) wt Part II 1. Steps involved in the initiation of cartilage formation 2. Signals regulating maturation of chondrocytes within a cartilage template 3. Factors controlling osteobastogenesis 4. Factors involved in osteoclastogenesis 5. Bone homeostasis 6. Bone repair - fractures 7. Joint formation 21