Except for the selfregulatory mechanism, elevated bone resorption and blood calcium levels induced by osteoclast maturation and activation also play a regulatory role in the pathway loop. An osteoclast is a large multinucleated cell and human osteoclasts on bone typically have five nuclei and are 150200 m in diameter. Osteoclastactivating factor definition of osteoclast. An osteoclast is a type of bone cell that breaks down bone tissue. Some genes act during the formation andor survival of the osteoclast precursor cell pu. These results suggest that rankpositive osteoclast progenitors are positively regulate the signal of bone formation. Macrophage colonystimulating factor mcsf induces myeloid precursors to differentiate to osteoclast precursors that express rank receptor activator of nf. During osteoclast differentiation on nonmineralized matrix, podosomes evolve from clusters into unstable small podosome rings, which fuse and expand toward the periphery of the cell to form a belt, 2 to 3. New members of the tnf receptor ligand family namely receptor activator of nuclear factor. Rolofylline, an adenosine a1 receptor antagonist, inhibits. Activation of adenosine a2a receptor reduces osteoclast. Molecular understanding of osteoclast differentiation and physiology doi.
In summary, osteoclastic bone resorption directly activates osteoblast function and osteoclasts are involved in normal bone morphogenesis. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Osteoclast differentiation and activation of raw 264. Osteoclasts are cells of hematopoietic origin with a unique property of dissolving bone. Six to 12 weekold c57bl6 mice jackson laboratories were sacrificed and bone marrow harvested and processed as we previously reported. Molecular regulation of osteoclast activity springerlink. In conclusion, osteoblastsstromal cells are involved in all of the processes of osteoclast development, such as differentiation, survival, fusion, and activation of osteoclasts. Interleukin il17producing helper t th17 cells have stimulatory effects on osteoclastogenesis and play an important role in the pathogenesis of rheumatoid arthritis through il17, whereas th1 and th2 cells have inhibitory effects on osteoclastogenesis through interferon. Pasteurella multocida toxin induced osteoclastogenesis. Bone is not essential for osteoclast activation karen fuller, jade l. Stat3 controls osteoclast differentiation and bone homeostasis by. Discovery of the rank signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass.
These may have dozens of nuclei, and typically express major. Thus, reducing osteoclast numbers andor decreasing the bone resorbing activity of osteoclasts are two common therapeutic approaches for the treatment of hyperresorptive skeletal diseases. Prior work demonstrates that stimulation of camppka signalling lead to activation of the mapk cascade and activation of erk12, p38 and jnk are wellestablished signalling intermediates in. The generation and study of osteoclasts was forever changed by the identification of mcsf and rankl as the essential cytokines responsible for the differentiation of haematopoietic stem cells into mature and functional osteoclasts. This chapter describes the methods for osteoclast formation in vitro in the presence and absence of osteoblasts, and for pitformation assay using dentine slices and osteoclasts formed in vitro. Characterization of the osteoclast lineage cells in these mice provided important information on the stage of differentiation affected fig. Osteoclast definition of osteoclast by the free dictionary.
Osteoclast differentiation factor odf induces osteoclastlike cell formation in human peripheral blood mononuclear cell cultures. Osteoblastsstromal cells can now be replaced with rankl and mcsf in dealing with the whole life of osteoclasts. Molecular understanding of osteoclast differentiation and. Molecular understanding of osteoclast differentiation and physiology na kyung lee department of biomedical laboratory science, soonchunhyang university college of medical science, asan, korea endocrinol metab 254. This ros is known to stimulate osteoclast differentiation and participate in early signaling events associated with osteoclast activation for bone resorption hall et al. Thiazolidinediones on ppar the roles in bone remodeling. Inhibition of osteoclast activation by phloretin through.
Transforming growth factor beta 1 induces cxcl16 and. Semaphorin 3a produced by osteoblasts inhibits ranklinduced osteoclast differentiation through the suppression of immunoreceptor tyrosinebased activation motif signals. We previously reported that adenosine, acting at adenosine a 2a receptors a 2a r, inhibits osteoclast oc differentiation in vitro a 2a r activation oc formation reduces by half and in vivo. B and trem2 triggering receptor expressed by myeloid cells2 receptors. Moreover, adenosine a 2a r activation directly suppressed the secretion of mcsf, a cytokine required for differentiation of osteoclast precursor cells, by wear particlestimulated calvaria. To date, other negative regulators of osteoclast differentiation, such as interferon regulatory factor 8 irf8. Osteoclast activation is a critical cellular process for pathological bone resorption, such as erosions in rheumatoid arthritis ra or generalized bone loss. Generation of osteoclasts in vitro, and assay of osteoclast. When osteoclastinducing cytokines are used to convert macrophages to osteoclasts, very large cells that may reach 100 m in diameter occur. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. B and p38 map kinase, elevation of calcium levels, and induction of cfos are essential for osteoclast differentiation 2,3. Trap expression, osteoclastlike cells in resorption lacunae at the bonepannus interface express the calcitonin receptor ctr. An osteoclast from the greek words for bone and broken is a type of bone cell that removes bone tissue by removing the bones mineralized matrix. One possible explanation for diminished osteoclast differentiation by these cells could be enhanced activation of amp kinase, which diminishes osteoclast differentiation induced by exposure to rankl lee et al.
The molecular understanding of osteoclast differentiation. Osteoclast differentiation and activation request pdf. Many osteoclast precursor cell lines differentiate into osteoclasts in response to stimulation by mcsf and srankl 1,2. Characterization of the osteoclastlineage cells in these mice provided important information on the stage of differentiation affected fig. Mechanisms by which cells of the osteoblast lineage. At the crossroads of the adipocyte and osteoclast differentiation. Osteoclasts are specialized cells derived from the monocytemacrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. In fact, osteoclasts are markedly activated after rankl binding to the cognate rank. Tak1 is essential for osteoclast differentiation and is an.
In in vitro mouse and human osteoclast differentiation models, expression of the ctr occurs during the terminal stage of osteoclast differentiation, and activation coincides with the competence of the cell to resorb bone. Osteoclastic bone resorption directly activates osteoblast. Balanced movement of osteoclast precursors toward and away from, bone surfaces has recently emerged as an important regulator of osteoclast differentiation in vivo. Suppresses osteoclast differentiation through inhibiting. Osteoclastderived activity in the coupling of bone. Osteoclast definition of osteoclast by medical dictionary. Regulation of osteoclast differentiation by t cells in openi. Simvastatin inhibits osteoclast differentiation by. Tak1 is essential for osteoclast differentiation and is an important modulator of cell death by apoptosis and necroptosis betty lamothe, yun ju lai, min xie, michael d.
Factors that regulate osteoclast differentiation an update. Cloning and characterization of osteoclast precursors from. The identification of rankrankl signaling as the main signal regulating osteoclast differentiation was a major breakthrough in the bone biology field. Review article regulation of osteoclast differentiation by. These culture systems have made it possible to investigate each step of osteoclast development and function separately. May 15, 2003 discovery of the rank signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Opg produced by b cells inhibits osteoclast formation by binding to rankl. A ranklbased osteoclast culture assay of mouse bone marrow to investigate the role of mtorc1 in osteoclast formation. Rank is the receptor for rankl and its role in osteoclast differentiation and activation is well established in vitro, as well as in mice and in humans 15, 2628. The understanding of osteoclasts oc differentiation and activation comes from the analysis of a family of biologically related tumor necrosis factor tnf and. Osteoclast derivation from mouse bone marrow protocol. The role played by cell substrate interactions in the. Regulation of osteoclast differentiation by t cells in. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue.
However, in contrast to mscs, activation of these adipogenic transcription factors in hscs promotes the differentiation of osteoclast precursors. Wnt5a, produced by osteoblasts, enhances osteoclast differentiation by upregulating rank expression through activation of the noncanonical wnt pathway. May 15, 2003 recent breakthroughs in our understanding of osteoclast differentiation and activation have come from the analysis of a family of. However, increased bone fracture risk in diabetic individuals treated with tzds is one of the reported side effects. Regulators of osteoclast differentiation and cellcell fusion. Homologues of notch receptors and ligands, first studied in drosophila, have been identified in nearly all metazoans phyla, from caenorhabditis elegans to. Opg is a soluble receptor for rankl that inhibits osteoclast differentiation in vitro as a decoy receptor 15. Ranklmediated osteoclast formation from murine raw 264. Retinoid x receptors orchestrate osteoclast differentiation. Trance tumor necrosis factorrelated activationinduced cytokine is a type 2 membrane protein which belongs to the tnf su. The osteoclast differentiation factor receptor activator of nfb ligand rankl increased the expression of adenylate cyclase 3 ac3, accompanied by a rise in the intracellular camp level in osteoclasts. Rank, rankl and osteoprotegerin in arthritic bone loss scielo. B ligand rankl, and osteoprotegerin opg produced by osteoblasts play major roles in the regulation of osteoclast differentiation.
Role of notch signaling in osteoimmunologyfrom the. However, on the molecular level the process of bone loss remains largely uncharacterised. Transcriptional program of mouse osteoclast differentiation. The osteoclasts, multinucleared cells originating from the hematopoietic monocytemacrophage lineage, are responsible for bone resorption. Thus, it is likely that adenosine a 2a r stimulation both suppressed the secretion of osteoclast differentiation factors and inhibited osteoclast response. Mem supplemented with 10% vv fbs, 100 ngml rankl, and 25 ngml mcsf differentiation medium. Opg binds and neutralizes rankl, leading to a block in osteoclastogenesis and. Among many factors triggering excessive osteoclast activity, cytokines such as il1 or tumour necrosis factor tnf. Whereas cell lines have frequently provided an invaluable research tool and are widely used to decipher mechanisms involved in osteoblast ob differentiation and bone formation, no immortalized cell lines for mature ocs exist and the few preoc cell lines that have been reported either do not undergo full oc differentiation 2, 3 or involve. Another osteoclastdeficient osteopetrotic model, opop mice, cannot produce functionally active mcsf because of a frame shifttype mutation in the coding region of the mcsf gene. Biochemical and biophysical research communications, 246 1, 199204. Osteoclast differentiation factor odf induces osteoclast. Activation of calcium signaling also stimulates nfatc1 expression.
Osteoclastogenesis is mainly regulated by signaling pathways activated by rank and immune receptors, whose ligands are expressed on the surface of osteoblasts. Retinoid x receptors orchestrate osteoclast differentiation and postnatal bone remodeling maria p. Aug 21, 20 one possible explanation for diminished osteoclast differentiation by these cells could be enhanced activation of amp kinase, which diminishes osteoclast differentiation induced by exposure to rankl lee et al. Pigs suffering from an infection with toxigenic pasteurella multocida strains develop atrophic rhinitis characterised by a loss of turbinate bones and conchae. So far, macrophage colonystimulating factor mcsf, receptor activator of nuclear factor. Except for the selfregulatory mechanism, elevated bone resorption and blood calcium levels. Triterpenoid saponin w3 from anemone flaccida suppresses.
It has been our experience that the in vitro cultivation of osteoclasts from bone marrow is largely dependent on seeding density. Multiple lines of evidence have established that osteoclasts are required for physiologic bone resorption and pathological bone loss in inflammatory disorders. In this study we discovered new signaling pathways involving camp regulators that modulate nfatc1 during osteoclastogenesis. Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity.
Here we summarize the current understanding of osteoclast differentiation and activation in the context of osteoimmunology. For a better understanding how adenosine a 2a r stimulation regulates oc differentiation, we dissected the signalling pathways involved in a 2a r signalling. This is an attempt to give a birdseyeview of the players in osteoclast formation and differentiation in a brief and concise manner. It was the identification of rankl that lead to this, when it was recently identified as the major regulator of osteoclast formation, differentiation and survival 1618. Osteoclast differentiation is inhibited by osteoprotegerin opg, which is. Once activated, osteoclasts move to areas of microfracture in the bone by. Rankl, which is expressed in activated t cells, has the capacity to induce osteoclast differentiation by directly binding rank on osteoclast precursor cells.
Regulation of osteoclast differentiation by t cells in rheumatoid arthritis. Isolation of differentiated osteoclasts from bone is technically challenging, but with the discovery that mcsf and rankl are sufficient for osteoclast differentiation came the ability to generate multinucleated. Lhx2 regulates bone remodeling in mice by modulating rankl. There is redundancy in the roles of the different ectonucleotidases in the catabolism of nucleotides to adenosine. Osteoprotegerin produced by osteoblasts is an important. Boneresorbing osteoclasts are formed from a monocytemacrophage lineage under the strict control of boneforming osteoblasts. Specifically, the authors show that myc drives metabolic reprogramming in osteoclasts and that myc induces estrogen receptorrelated receptor. As mentioned above, the naturally occurring and genetically modified osteopetrotic mice revealed a number of essential genes for osteoclast differentiation and activation. A ranklbased osteoclast culture assay of mouse bone.
Prior work demonstrates that stimulation of camppka signalling lead to activation of the mapk cascade and activation of erk12, p38 and jnk are wellestablished signalling intermediates in osteoclast differentiation. We propose that osteoclasts transmit information to the osteoblast lineage to support the coupling of bone formation to resorption. Here, we report the novel therapeutic action of simvastatin in osteoclastogenesis and osteoprotection, demonstrated by the ability of simvastatin to suppress osteoclast formation in vitro and in vivo. Molecular understanding of osteoclast differentiation and physiology na kyung lee. In the osteoclast differentiation pathway, rankl binds to the rank receptor and then stimulates intracellular ros generation. B, ap1, creb, mitf and nfatc1 activation via traf6 recruitment and the mapks, akt, vav3 and csrc signaling cascades to promote the differentiation of oc precursors into mature ocs. Osteoclast differentiation 103 ferentiation through induction of a second transcription factor nfatc1, which is critical for ocl differentiation. Discovery of the rank signalling pathway in the osteoclast has. Finally, therapeutic strategies designed to target osteoclast precursor movement are beginning to show promising results for the treatment of osteoporosis in mouse models. Erk5 activation is essential for osteoclast differentiation. Generation and culture of osteoclasts pubmed central pmc. Recent breakthroughs in our understanding of osteoclast differentiation and activation have come from the analysis of a family of. All protocols were approved by the mayo clinic iacuc prior to the start of the studies. We found that in vitro, irf4 expression is upregulated during osteoclast differentiation induced by rankl receptor activator of nuclear.
Cloning and characterization of osteoclast precursors from the raw264. Modulation of osteoclast differentiation and function by the. A 2a r activation inhibits osteoclast differentiation by activation of erk12. In addition remarkable discoveries have been made to broaden the knowledge of the molecular mechanisms of osteoclast formation and differentiation. Pasteurella multocida toxin pmt is a potent inducer of osteoclast formation. Some genes act during the formation and or survival of the osteoclast precursor cell pu. The notch signaling pathway is an evolutionary conserved mechanism to transmit signals upon ligandreceptor binding of adjacent cells, thereby enabling them to adopt different fates souilhol et al. Diseases of bone loss are a major public health problem. Osteoclast activation is a critical cellular process for pathological bone resorption, such as erosions in rheumatoid arthritis ra or generalized. Stimulation of osteoclast formation by rankl requires. Protocols for generation of human osteoclasts in vitro have been described, but they often result in cells of low activity, raising questions on cell phenotype and suitability of such assays for screening of bone resorption inhibitors. For a better understanding how adenosine a 2a r stimulation regulates oc differentiation, we dissected the signalling pathways involved in a 2a r.
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