Metabolic Bone And Associated Diseases
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correlation of obesity, diabetes, arterial calcification, metastasis with bone mineral density.
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Metabolic Bone And Associated Diseases
- 1. Metabolic bone- Associated Diseases Vinod Naneria Choithram Hospital & Research Centre Indore, India
- 9. Leptin, is a 16 kDa protein derived from white fat cells. It regulates the size of the body’s fat load (i.e., energy reserves) other functions: bone growth. The evidence so far indicates that leptin controls bone growth in two ways. It stimulates the release of an undefined hypothalamic osteoblast-inhibiting factor(s), which limits the amount of bone matrix that osteoblasts can make. Leptin is a bone anabolic factor that directly stimulates bone growth by inducing osteoblasts to make IGF-I (insulin-like growth factor-I) and inhibiting osteoclast generation.
- 10. Leptin indirectly restrains but directly stimulates bone formation. Leptin from fat cells or from late-stage, matrix-mineralizing osteoblasts inhibits osteoclast generation by stimulating the production of the anti-osteoclastogenic osteoprotegerin (OPG) and reciprocally reducing the pro-osteoclastogenesis RANK by marrow osteoblastic cells. Leptin also causes osteoblastic cells to make IGF-I and TGF-betas, which in turn stimulate the proliferation of osteoprogenitor cells (osteoprogenitor), stimulate bone matrix mineralization, and prevent osteoblasts and osteocytes from committing apoptotic suicide. Leptin also stimulates hypothalamus cells to make some kind of hypothalamic osteoblast inhibitory factor (HOBIF) or trigger some neural process that restrains osteoblasts' matrix-making activity. Leptin
- 11. Leptin inhibits the release of neuropeptide Y (NPY), which prevents the activation of Y2R receptors, signals that would otherwise mimic HOBIF's osteoblast-restraining activity. But, if Leptin -- and with it, HOBIF production -- should decrease, NPY production would surge, and the osteoclast-suppressing signals from Y2R receptors would take over from HOBIF. However, according to the experience so far with rodents, injecting leptin can override the inhibitory brain-based mechanisms and directly stimulate bone formation. Leptin drives ovarian cycling by stimulating the secretion of gonadotropin-releasing hormone (GnRH) and thus follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release. Therefore, the lack of Leptin and the consequent estrogen shortage in obese Ob(Lep)-/- mice should cause bone loss because of a normally estrogen-suppressed population explosion of bone-destroying osteoclasts, similar to what occurs in the bones of ovariectomized rodents, ovariectomized monkeys, and postmenopausal women. Leptin
- 12. The Bone-Related Pieces of the Leptin Puzzle Both Ob(Lep)-/- mice without leptin, as well as Db-/- mice with disabled LepRb receptors that can make leptin but can't respond to it, have an abnormally high bone mass that appears before the animals start loading up with fat and is therefore not just a trivial consequence of bones adjusting to increased body weight. The high bone mass in thin A-ZIP/F-I mice that do not have leptin-making white fat cells provides proof that it is a lack of leptin, and not excessive weight, that is responsible for high bone mass. The high bone mass is not, due to more osteoblasts being generated to face the osteoclast onslaught. Only a normal number of osteoblasts are available to face the osteoclasts. These are super-osteoblasts that can make twice as much matrix as normal osteoblasts. Injecting leptin intracerebrally causes the bones of Ob(Lep)-/- mice to lose mass; thus, it seems that leptin restrains osteoblast activity by stimulating the production of some kind of hypothalamic osteoblast inhibitory factor (HOBIF) or neural process. Thus was found the first of the bone-related pieces of the leptin puzzle.
- 13. Obese (fa/fa) Zuker rats, like Ob(Lep)-/- mice, cannot make leptin and also have supernormal bone mass, which probably means that rats have the same leptin-dependent, brain-based, osteoblast-restraining mechanism as mice. On the other hand, the direct responses of rat bone cells and bones to injected leptin are unequivocally positive or anabolic. Primary rat osteoblasts and ROS 17/2.8 osteoblastic osteosarcoma cells have LepRb receptors. And intraperitoneally infused recombinant human leptin in tail-suspended rats prevents the reduction of tibial metaphyseal trabecular bone BMD resulting from hind limb disuse (ie, the lack of normal bone-maintaining strain pulses produced by the hind limbs of tail-suspended rats), and it actually increases femoral diaphyseal bone BMD in the tail-suspended rats. Leptin has also been found to reduce ovariectomy-induced bone loss in rats. Incidentally, this observation suggests that leptin might eventually be used to prevent the loss of bone in astronauts during long voyages in space. Leptin
- 19. Research over the past two years has provided new clinical evidence that the currently prescribed TZDs increase fracture risk and bone loss, at least in women. Combined with the findings from rodent and in vitro models, these clinical results suggest that activation of PPAR can play a role in bone loss. With the widespread use of TZDs as a diabetes treatment, further research is needed to delineate the groups that are most susceptible to TZD-induced osteoporosis, to determine the rate of bone loss with TZD treatment beyond 16 weeks, to assess the effects of TZDs on marrow adiposity, cortical and trabecular bones, and to identify treatments to prevent TZD-induced fracture risk. Addressing these questions will advance our ability to prevent TZD-induced osteoporosis and will provide a better understanding of the role of PPAR activation in bone metabolism. BMD + Type 2 DM Rx
- 21. Associations between coronary disease and serum OPG and RANKL levels
- 26. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies. RANK Ligand and Osteoprotegerin
- 38. Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastasis to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to non bone sites. These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth. parathyroid hormone-related peptide (PTH-rP) hypercalcemia Bone Metastasis
- 40. The role of bone-derived TGF-beta in the development and progression of bone metastasis was studied by transfecting MDA-MB-231 cells with a cDNA encoding a TGF-beta type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF-beta. Stable clones expressing this mutant receptor (MDA/TbetaRIIdeltacyt) did not increase PTH-rP secretion in response to TGF-beta stimulation compared with controls of untransfected MDA-MB-231 or those transfected with the empty vector. Data suggest that PTH-rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF-beta responsiveness of breast carcinoma cells may be important for the expression of PTH-rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be responsible for the alacrity with which breast carcinoma grows in bone. parathyroid hormone-related peptide (PTH-rP) hypercalcaemia Bone Metastasis
- 41. Breast carcinoma commonly metastasizes to the skeleton in patients with advanced disease, hypercalcemia, fracture, and nerve-compression syndromes. The bone destruction is mediated by the osteoclast. Tumor-produced parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process. Transforming growth factor beta (TGFbeta), which is abundant in bone matrix and is released as a consequence of osteoclastic bone resorption, may promote breast carcinoma osteolysis by stimulating PTHrP production by tumor cells. These data indicate a central role for TGFbeta in the pathogenesis of osteolytic bone metastases from breast carcinoma by 1) the induction of PTHrP through the Smad signaling pathway and 2) the potentiation of ER-alpha-mediated transcription induced by a constitutively active ER-alpha. Understanding the mechanisms of osteolysis at a molecular level will generate more effective therapeutic agents for patients with this devastating complication of cancer. parathyroid hormone-related peptide (PTH-rP) hypercalcemia Bone Metastasis
- 50. Bon Voyage
Editor's Notes
- Low body mass is a risk factor for osteoporotic fractures.
- Leptin indirectly restrains but directly stimulates bone formation. Leptin from fat cells or from late-stage, matrix-mineralizing osteoblasts inhibits osteoclast generation by stimulating the production of the anti-osteoclastogenic osteoprotegerin (OPG) and reciprocally reducing the pro-osteoclastogenesis RANK by marrow osteoblastic cells. Leptin also causes osteoblastic cells to make IGF-I and TGF-betas, which in turn stimulate the proliferation of osteoprogenitor cells (osteoprogenitor), stimulate bone matrix mineralization, and prevent osteoblasts and osteocytes from committing apoptotic suicide. But leptin also stimulates hypothalamus cells to make some kind of hypothalamic osteoblast inhibitory factor (HOBIF) or trigger some neural process that restrains osteoblasts' matrix-making activity. And leptin inhibits the release of neuropeptide Y (NPY), which prevents the activation of Y2R receptors, signals that would otherwise mimic HOBIF's osteoblast-restraining activity. But, if leptin -- and with it, HOBIF production -- should decrease, NPY production would surge, and the osteoclast-suppressing signals from Y2R receptors would take over from HOBIF. However, according to the experience so far with rodents, injecting leptin can override the inhibitory brain-based mechanisms and directly stimulate bone formation.
- But does leptin itself restrain bone growth? There is convincing evidence that leptin actually directly stimulates bone growth.
- subject Category: Metabolic bone disease Fat targets for skeletal health Masanobu Kawai 1 , Maureen J. Devlin 2 & Clifford J. Rosen 1 About the authors topof pageAbstract
- subject Category: Metabolic bone disease Fat targets for skeletal health Masanobu Kawai 1 , Maureen J. Devlin 2 & Clifford J. Rosen 1 About the authors topof pageAbstract
- Osteoporos Int. 2008 Feb;19(2):129-37. Epub 2007 Sep 28. Links Skeletal consequences of thiazolidinedione therapy. Grey A . Department of Medicine, University of Auckland, Auckland, New Zealand. a.grey@auckland.ac.nz
- This study demonstrates that short-term therapy with rosiglitazone, a commonly prescribed PPAR- agonist, inhibits bone formation and accelerates bone loss in healthy postmenopausal women. These data are consistent with those from in vitro and animal studies demonstrating that PPAR- signaling negatively regulates osteoblast function (bone formation) and bone mass ( 7 , 8 , 11 , 13 , 14 ). The pattern of alteration of bone remodeling that we observed in response to rosiglitazone is similar to that seen after the initiation of glucocorticoid therapy ( 26 ). The uncoupling of bone formation from resorption by glucocorticoids is accompanied by early and rapid bone loss and an increased risk of fragility fractures ( 27 ). Our data suggest that rosiglitazone may also promote rapid bone loss; longer-term studies are needed to determine whether the rate of loss we observed is sustained. Because patients with type 2 diabetes may have an increased risk of fragilityfractures ( 16 , 17 , 18 , 19 , 20 ), the possibility that one of the therapies commonly used to treat the disease may be increasing that risk is a cause for concern. The increasing use of thiazolidinediones in other clinical conditions characterized by insulin resistance ( 28 , 29 ), including impaired glucose tolerance ( 30 ), is a further reason to fully characterize their long-term skeletal effects. We therefore suggest that skeletal safety end points should be added to existing and planned randomized trials of PPAR- agonists so that the skeletal effects of thiazolidinediones can be studied over a longer period.Although preclinical studies have consistently reported that rosiglitazone impairs osteoblast function ( 13 , 14 , 31 , 32 ), conflicting in vitro data exist as to whether PPAR- signaling affects osteoclastogenesis ( 7 , 9 , 10 ). Our data suggest that PPAR- agonists do not influence bone resorption in vivo , a finding consistent with those of in vivo studies in rodents ( 11 , 13 , 14 ). The limited preclinical data that are available on the skeletal effects of pioglitazone, the other commonly prescribed thiazolidinedione, suggest that it has comparable actions with those of rosiglitazone ( 33 , 34 ). Whether there is a class effect of thiazolidinediones on skeletal homeostasis is uncertain, with recent preclinical studies of new compounds reporting both adverse ( 35 ) and neutral ( 36 ) effects in rodent models. Currently there are few data available on the skeletal actions of thiazolidinediones in humans. Uncontrolled studies of Japanese subjects with type 2 diabetes treated with troglitazone, a PPAR- agonist no longer in clinical use, reported significant reductions in markers of both bone formation and resorption after 1 month, but values returned to baseline by 1 yr ( 37 , 38 ). More recently an analysis of the small number (n = 69) of diabetic subjects taking thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone) in the Health, Aging, and Body Composition observational study reported accelerated bone loss in over 4 yr in women but not men ( 15 ). After our manuscript was submitted, Kahn et al . ( 39 ) reported a higher incidence of fractures, detected as adverse events, in female diabetic subjects randomized to receive rosiglitazone, compared with those randomized to receive either metformin or glyburide, during a 4 yr study of glycemic durability of oral monotherapies. Our findings provide rigorous evidence for a detrimental effect of PPAR- agonists on the postmenopausal femaleskeleton. Whether there is a gender difference in the skeletal response to thiazolidinediones can be determined only by a randomized, controlled trial in men. The mechanism(s) by which rosiglitazone alters bone remodeling likely involves direct effects on osteoblast development and function, but the possibility of indirect skeletal actions also exists. Adipose tissue is a target for PPAR- agonists, and some adipokines influence bone cell function. Thiazolidinediones may decrease circulating levels of leptin ( 38 ), the peripheral actions of which include osteoblast anabolism ( 40 ). The insulin-sensitizing actions of PPAR- agonists lower circulating levels of insulin ( 1 ) and therefore are likely to reduce levels of the cosecreted pancreatic ß-cell peptide amylin, each of which is anabolic to osteoblasts ( 41 , 42 ).
- Atherosclerotic calcification occurs in the intima, potentially leading to luminal obstruction. Medial artery calcification, on the other hand, often seen in patients with diabetes and renal failure, occurs in the tunica media, and can lead to abnormal vascular compliance. Diffuse calcium phosphate deposition can also occur when the physiological calcium phosphate solubility threshold is exceeded. Vascular calcification was in the past considered a passive process, a degenerative consequence of aging. It is now understood that calcium deposition in the vasculature is an active and regulated process akin to bone formation. Calcified atherosclerotic arteries contain tissue that is histomorphologically indistinguishable from bone. A subpopulation of artery wall cells (calcifying vascular cells) has the ability to undergo osteoblastic differentiation. These cells may express various bone matrix proteins and skeletal regulatory factors that have been demonstrated in human calcified plaque, including osteocalcin, bone sialoprotein, osteonectin, collagen I, alkaline phosphatase, Msx-2, and Cbfa-1. Arterialcalcification could therefore be said to recapitulate osteogenesis.
- RANK Ligand and Osteoprotegerin. Paracrine Regulators of Bone Metabolism and Vascular Function Michael Schoppet ; Klaus T. Preissner ; and Lorenz C. Hofbauer * From the Divisions of Cardiology (M.S.) and Gastroenterology, Endocrinology and Metabolism (L.C.H.), Department of Medicine, Philipps-University, Marburg, and Institute for Biochemistry (K.T.P.), Faculty of Medicine, Justus-Liebig-University, Giessen, Germany. * To whom correspondence should be addressed. E-mail: [email_address] . Abstract —In 1997, investigators isolated a secreted glycoprotein that blocked osteoclast differentiation from precursor cells, prevented osteoporosis (decreased bone mass) when administered to ovariectomized rats, and resulted in osteopetrosis (increased bone mass) when overexpressed in transgenic mice. Since then, the isolation and characterization of the protein named osteoprotegerin (OPG) has stimulated much work in the fields of endocrinology, rheumatology, and immunology. OPG functions as a soluble decoy receptor for receptor activator of nuclear factor- B ligand (RANKL, or OPG ligand) and shares homologies with other members of the tumor necrosis factor receptor superfamily. OPG acts by competing with the receptor activator of nuclear factor- B, which is expressed on osteoclasts and dendritic cells for specifically binding to RANKL. RANKL is crucially involved in osteoclast functions and bone remodeling as well as immune cell cross-talks, dendritic cell survival, and lymph node organogenesis. More recently, emerging evidence from in vitro studies and mouse genetics attributed OPG an important role in vascular biology. In fact, OPG could represent the long sought-after molecular link between arterial calcification and bone resorption, which underlies the clinical coincidence of vascular disease and osteoporosis, which are most prevalent in postmenopausal women and elderly people. Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. Hofbauer LC , Heufelder AE . Division of Gastroenterology, Endocrinology and Metabolism, Zentrum für Innere Medizein, Philipps University, Marburg, Germany. hofbauer@post.med.uni-marburg.de Receptor activator of nuclear factor (NF-kappaB) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways. The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor alpha, interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor gamma, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies. Cytokine Growth Factor Rev. 2004 Dec;15(6):457-75. Links The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Theoleyre S , Wittrant Y , Tat SK , Fortun Y , Redini F , Heymann D . EA 3822, INSERM ESPRI, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France. The past decade has seen an explosion in the field of bone biology. The area of bone biology over this period of time has been marked by a number of key discoveries that have opened up entirely new areas for investigation. The recent identification of the receptor activator of nuclear factor kappaB ligand (RANKL), its cognate receptor RANK, and its decoy receptor osteoprotegerin (OPG) has led to a new molecular perspective on osteoclast biology and bone homeostasis. Specifically, the interaction between RANKL and RANK has been shown to be required for osteoclast differentiation. The third protagonist, OPG, acts as a soluble receptor antagonist for RANKL that prevents it from binding to and activating RANK. Any dysregulation of their respective expression leads to pathological conditions such as bone tumor-associated osteolysis, immune disease, or cardiovascular pathology. In this context, the OPG/RANK/RANKL triad opens novel therapeutic areas in diseases characterized by excessive bone resorption. The present article is an update and extension of an earlier review published by Kwan Tat et al. [Kwan Tat S, Padrines M, Theoleyre S, Heymann D, Fortun Y. IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev 2004;15:49-60]. : J Investig Med. 2006 Nov;54(7):395-401.Links Role of osteoprotegerin and its ligands and competing receptors in atherosclerotic calcification. Tintut Y , Demer L . Department of Medicine, University of California, Los Angeles, Los Angels, CA, USA. Vascular calcification significantly impairs cardiovascular physiology, and its mechanism is under investigation. Many of the same factors that modulate bone osteogenesis, including cytokines, hormones, and lipids, also modulate vascular calcification, acting through many of the same transcription factors. In some cases, such as for lipids and cytokines, the net effect on calcification is positive in the artery wall and negative in bone. The mechanism for this reciprocal relation is not established. A recent series of reports points to the possibility that two bone regulatory factors, receptor activator of NF-kappaB ligand (RANKL) and its soluble decoy receptor, osteoprotegerin (OPG), govern vascular calcification and may explain the phenomenon. Both RANKL and OPG are widely accepted as the final common pathway for most factors and processes affecting bone resorption. Binding of RANKL to its cognate receptor RANK induces NF-kappaB signaling, which stimulates osteoclastic differentiation in preosteoclasts and induces bone morphogenetic protein (BMP-2) expression in chondrocytes. A role for RANKL and its receptors in vascular calcification is spported by several findings: a vascular calcification phenotype in mice genetically deficient in OPG; an increase in expression of RANKL, and a decrease in expression of OPG, in calcified arteries; clinical associations between coronary disease and serum OPG and RANKL levels; and RANKL induction of calcification and osteoblastic differentiation in valvular myofibroblasts.
- 1: Curr Drug Discov Technol. 2008 Sep;5(3):263-8. Links RANKL/RANK/OPG: key therapeutic target in bone oncology. Ando K , Mori K , Rédini F , Heymann D . Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.
- 1: Expert Rev Anticancer Ther. 2007 Feb;7(2):221-32. Links Baud'huin M , Duplomb L , Ruiz Velasco C , Fortun Y , Heymann D , Padrines M . Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, EA3822, Nantes, F-44035 France. marc.baud-huin@etu.univ-nantes.fr
- 1 : Cancer. 2003 Feb 1;97(3 Suppl):834-9. Links Mechanisms of osteolytic bone metastases in breast carcinoma. Käkönen SM , Mundy GR . University of Texas Health Science Center, Department of Molecular Medicine, Institute for Drug Development, San Antonio, Texas 78229-3900, USA
- Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases. Prostate cancer cells produce a variety of pro-osteoblastic factors that promote bone mineralization. For example, both bone morphogenetic proteins and endothelin-1 have well recognized pro-osteoblastic activities and are produced by prostate cancer cells. In addition to factors that enhance bone mineralization prostate cancer cells produced factors that promote osteoclast activity. Perhaps the most critical pro-osteoclastogenic factor produced by prostate cancer cells is receptor activator of NF B ligand (RANKL), which has been shown to be required for the development of osteoclasts. Blocking RANKL results in inhibiting prostate cancer-induced osteoclastogenesis and inhibits development and progression of prostate tumor growth in bone. These findings suggest that targeting osteoclast activity may be of therapeutic benefit. However, it remains to be defined how prostate cancer cells synchronize the combination of osteoclastic and osteoblastic activity. We propose that as the bone microenvironment is changed by the developing cancer, this in turn influences the prostate cancer cells' balance between pro-osteoclastic and pro-osteoblastic activity. Accordingly, the determination of how the prostate cancer cells and bone microenvironment crosstalk are important to elucidate how prostate cancer cells modulate bone remodeling. © 2003 Wiley-Liss, Inc.
- Cancer. 1997 Oct 15;80(8 Suppl):1546-56. Links Mechanisms of bone metastasis. Mundy GR . University of Texas Health Science Center, San Antonio, USA.
- Links 1: Cancer. 1997 Oct 15;80(8 Suppl):1572-80. Parathyroid hormone-related protein and bone metastases. Guise TA . Department of Medicine, University of Texas Health Science Center at San Antonio, 78284-7877, USA.
- : Histol Histopathol. 2009 Feb;24(2):235-42. Links Receptor activator of nuclear factor-kappa B ligand (RANKL) stimulates bone-associated tumors through functional RANK expressed on bone-associated cancer cells? Mori K , Ando K , Heymann D , Rédini F . Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan. kanchi@belle.shiga-med.ac.jp
- 1: Clin Orthop Relat Res. 2003 Oct;(415 Suppl):S32-8. Links Transforming growth factor-beta in osteolytic breast cancer bone metastases. Guise TA , Chirgwin JM . Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Breast cancers frequently metastasize to the skeleton and cause bone destruction. Tumor cells secrete factors that stimulate osteoclasts. The consequent osteolytic resorption releases active factors from the bone matrix, in particular transforming growth factor-beta (TGF-beta). The released factors then stimulate tumor cell signaling, which causes breast cancer cells to make increased amounts of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), interleukin-11 (IL-11), and vascular endothelial growth factor (VEGF). Therefore, tumor cell-bone cell interactions cause a vicious cycle in which tumor cells stimulate bone cells to cause bone destruction. As a consequence, the local microenvironment is enriched with factors that fuel tumor growth in bone. Transforming growth factor-beta is of particular importance because it increases breast cancer production of PTHrP. Parathyroid hormone-related protein then stimulates osteoblasts to express RANK (receptor activator of nuclear factor kappa B) ligand, which in turns enhances osteoclast formation and activity. Breast cancer osteolytic metastasis can be interrupted at four points in the vicious cycle: by neutralizing PTHrP biologic activity, by blocking the TGF-beta signaling pathway in the tumor cells, by inhibiting PTHrP gene transcription, and by inhibiting bone resorption.