The physiology and pathophysiology of the osteoclast. Stem cells, leading to cells forming laying down new bone tissue. Benjamin ma, md, professor, chief, sports medicine and shoulder service, ucsf department of orthopaedic surgery, san francisco, ca. The molecular basis of osteoclast differentiation and. Mcsf is a key player in promoting the proliferation and survival of osteoclast precursor cells. Introduction calcitonin generelated peptide cgrp, a 37residue peptide produced in specific neurons by alternative splicing of the calcitonin gene, is an important neuropeptide involved in bone growth and metabolism 1. Osteoclasts are generated from myeloid progenitors. In addition remarkable discoveries have been made to broaden the knowledge of the molecular mechanisms of osteoclast formation and differentiation. Bone remodeling, nci thesaurus osteoclasts are derived through the fusion of cells of the monocytemacrophage lineage. Successful osteoclast formation was confirmed by trap staining figure 2a. The present study also indicates that ocif acts as a naturally occurring decoy receptor for odf in inhibiting signal transduction in human osteoclast formation. Mice lacking the cfos gene have overly dense bone and decreased bone resorption due to reduced osteoclast differentiation, indicating that cfos is an important mediator of osteoclast differentiation. Of note is the stable gene upregulation induced by mcsf and three waves of. When mouse spleen cells and osteoblastic cells isolated from fetal mouse calvariae were cocultured in the presence of 10 nm l.
Pdf osteoclasts are multinucleated cells of hematopoietic origin which are unique in their ability to resorb bone. Nov 08, 2012 osteoclast formation and differentiation. Opg is a secreted tnfrrelated protein that regulates bone density and bone mass in animals22,23, and upon. Osteoclast formation and activity increase in response to inactivity and low calcium blood levels, which causes bones to become thinner and weaker. Rankl may also bind to osteoprotegerin, a protein secreted mainly by cells of the osteoblast lineage which is a potent inhibitor of osteoclast formation by preventing binding of rankl to rank. Inhibiting its action blocks the resorptive effects of pth 33. Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. In addition to the calcineurinnfatc1 axis, calcium signaling activates the calmodulin. Loss of csrc results in formation of ocl that cannot. Of note is the stable gene upregulation induced by mcsf and three waves of gene regulation induced by rankl. Osteoclast progenitor cells are recruited from haematopoietic compartments, and then proliferate and differentiate toward mature osteoclasts.
Hyaluronic acid ha is a component of the extracellular matrix that has been shown to play an important role in bone formation, resorption, and mineralization both in vivo and in vitro. During this multistep differentiation process postmitotic osteoclast precursors progressively express osteoclastassociated markers, such as calcitonin receptor and tartrateresistant acid phosphatase, as they lose some of their. It contributes to both the bone modeling and remodeling processes through a complex extracellular mechanism, termed bone resorption, which removes the mineral and the organic bone matrix components. The coordinated development and function of boneforming osteoblasts and boneresorbing osteoclasts cells is critical for the maintenance of skeletal integrity and calcium homeostasis. The differentiation of oc precursors into mononuclear and multinucleated ocs is further modulated by rankl and mcsf signaling. The inhibition of osteoclast differentiation is via negative regulation of rankl and. Osteoclasts are large cells, derived from stem cells in the bone marrow that give rise to.
Odf is responsible for inducing not only differentiation, but also activation of osteoclasts. The molecular understanding of osteoclast differentiation. Because the actin cytoskeleton plays unique roles in osteoclast formation and activity, its organization and the functions of actinbinding regulatory proteins have been examined in numerous studies. Thereby tight celltocell contact and interaction between the osteoblasts and the newly recruited osteoclast precursor cells are needed. Osteoclast formation was found to require the expression, by osteoblastic cells or a subpopulation of bone marrow stromal cells, of an activity that specifically induces osteoclast formation stromal osteoclast. Collagen triple helix repeat containing 1, a novel secreted protein in. The osteoclasts, multinucleared cells originating from the hematopoietic monocytemacrophage lineage, are responsible for bone resorption. Breast cancer cells interact with osteoblasts to support.
Osteoclasts are multinucleated cells of monocytemacrophage origin that degrade bone matrix. The role of nfat in osteoclast formation takayanagi. B ligand regulate osteoclast differentiation and activity. Review article regulation of osteoclast differentiation by. Hence, a better understanding of the pathways leading to osteoclast differentiation is vital in successfully managing such diseases. Osteoblast lineage cells, whose mature form is responsible for bone formation, also regulate the differentiation of osteoclast precursors into osteoclasts. Osteoclast differentiation factor odf is a key mediator of pthinduced bone resorption. Rankl also has a function in the immune system, where it is expressed by t helper cells and is thought to be involved in dendritic cell maturation. Osteoclasts are multinucleated cells of hematopoietic origin which are unique in their ability to resorb bone. Osteoblastderived vegf regulates osteoblast differentiation.
Mar 09, 2016 while osteoblasts and osteocytes are responsible for the production of bone, osteoclasts break it down. Ab we have reported that osteoclast differentiation factor odf expressed on the plasma membrane of osteoblastsstromal cells is a ligand for osteoclastogenesis inhibitory factor ocif. A ranklbased osteoclast culture assay of mouse bone marrow. Bone is a dynamic tissue that is continuously being broken down and restructured in response to such influences as structural stress and the bodys requirement for calcium. A ranklbased osteoclast culture assay of mouse bone. Medcram medical lectures explained clearly 185,844 views. Mechanisms of mechanically induced osteoclastogenesis. An overview niroshani surangika soysa1,2, neil alles1,3, kazuhiro aoki 1 and keiichi ohya 1 section of pharmacology, department of biomatrix, graduate school, tokyo medical and dental university, japan 2 division of pharmacology, faculty of dental sciences, university of peradeniya, sri lanka.
Osteoclast differentiation factor odf induces osteoclast. We developed a coculture system with mouse spleen cells and osteoblastic cells to examine the role of osteoblasts in osteoclast formation. Two essential cytokines macrophage colonystimulating factor and the receptor activator of nuclear factor. A large multinucleate cell found in growing bone that resorbs bony tissue, as in the formation of canals and cavities. Using the present protocol, a large number of giant osteoclasts were seen on day 6. The endosteal surface had some areas of new bone formation but numerous. Transcriptional program of mouse osteoclast differentiation. Hscs undergo differentiation into oc precursors depending on the presence of pu. This is an attempt to give a birdseyeview of the players in osteoclast formation and differentiation in a brief and concise manner. A simplified schematic overview of changes in gene expression observed during osteoclast differentiation, together with characteristic examples, is provided on fig. Osteoclast regulation of bone formation mayo clinic.
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. 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. The osteoclast is the giant cell of bone phylogenically evolved to resorb the bone matrix. On the other hand, a specific promoter of osteoclast differentiation does seem likely to be a product of cells of the stromalosteoblast series. These culture systems have made it possible to investigate each step of osteoclast development and function separately. Osteoclast, large multinucleated cell responsible for the dissolution and absorption of bone. It has been our experience that the in vitro cultivation of osteoclasts from bone marrow is. Importantly, osteoblast numbers and bone formation were reduced, supporting that osteoclast tgf. An enhanced adipogenic versus osteogenic potential of bone marrow mesenchymal stem cells mscs has been linked to bone loss associated with diseases such as diabetes mellitus, as well as aging and. Osteoclast differentiation and activation request pdf. B and trem2 triggering receptor expressed by myeloid cells2 receptors. This chapter describes the methods for osteoclast formation in vitro in the presence and absence of osteoblasts, and for pit formation assay using dentine slices and osteoclasts formed in vitro. A breakthrough in our understanding of how osteoclastogenesis is regulated was the identification of opg, a soluble protein that blocked osteoclast formation in vitro and bone resorption in vivo.
Such advances in the understanding of the molecular mechanism of osteoclast differentiation are expected to lead to novel therapeutic approaches to bone diseases. Evidence in facour of this comes from studies of osteoclast generation in co. During this multistep differentiation process postmitotic osteoclast precursors progressively express osteoclast associated markers, such as calcitonin receptor and tartrateresistant acid phosphatase, as they lose some of their macrophage characteristics. Osteoclasts are generated from myeloid progenitors through a progression that involves the fusion of mononuclear precursor cells.
Osteoclast differentiation an overview sciencedirect. Osteoclastogenesis inhibitory factor ocif, also called opg is a secreted tnf receptor, which acts as a decoy receptor for odf. Skeletal quantity and quality are determined by processes of bone modeling and remodeling, which are undertaken by cells that build and resorb bone as they respond to mechanical, hormonal, and other external and internal signals. Osteoclastogenesis is mainly regulated by signaling pathways activated by rank and immune receptors, whose ligands are expressed on the surface of osteoblasts. Regulation of the differentiation and function of osteoclasts. Finally, osteoblastderived vegf stimulated osteoclast formation in the final remodeling phase of the repair process.
The identification of rankrankl signaling as the main signal regulating osteoclast differentiation was a major breakthrough in the bone biology field. As the sole bone resorptive cell type, osteoclasts possess a remarkably dynamic actin cytoskeleton that drives their function in this enterprise. Mechanisms involved in enhancement of osteoclast formation. Osteoclast differentiation and function is under the control of neighboring immature osteoblasts or bone lining cells of the endosteum or periosteum 15. Osteoclastlike cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. It has been our experience that the in vitro cultivation of osteoclasts from bone marrow is largely dependent on seeding density. Odf, together with colonystimulating factor1, is both necessary and sufficient to induce osteoclastogenesis. 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. Osteoclast article about osteoclast by the free dictionary.
Macrophage colonystimulating factor mcsf induces myeloid precursors to differentiate to osteoclast precursors that express rank receptor activator of nf. Osteoclastic definition of osteoclastic by the free. However, the rate of osteoclast formation, and thus bone resorption, outpaces the rate of osteoblast formation and bone regeneration, and tshrnull mice have severe osteoporosis abe et al. Mechanisms by which cells of the osteoblast lineage. Osteoclastogenesis is mainly regulated by signaling pathways activated by rank and immune receptors, whose ligands are. Furthermore, osteoblast and hypertrophic chondrocytederived vegf stimulated recruitment of blood vessels and osteoclasts and promoted cartilage resorption at the repair site during the periosteal endochondral ossification stage. An enhanced adipogenic versus osteogenic potential of bone marrow mesenchymal stem cells mscs has been linked to bone loss associated with diseases such as diabetes mellitus, as. Many other cytokines impact osteoclast formation by inducing rankl and mcsf, while. An osteoclast contains from three to several dozen nuclei and a great many lysosomes, whose hydrolytic enzymes upon release from the osteoclasts resorb the mineral matrix of bone and calcified cartilage.
Molecular mechanisms regulating the differentiation and function of osteoclasts have been elucidated since the previous edition of this book. Our understanding of the differentiation and function of osteoclasts has advanced deeply with advances in science. It is a large cell with separately identifiable, multiple nuclei. Osteoclasts are multinucleated cells of hematopoietic origin which are. Molecular understanding of osteoclast differentiation and. Osteoclast differentiation an overview sciencedirect topics. Generation of osteoclasts in vitro, and assay of osteoclast. Schematic representation of oc differentiation and activation. Osteoclast derivation from mouse bone marrow protocol. The osteoclasts are the mediators of the continuous destruction of bone. For osteoclasts to be formed, both hematopoietic progenitor cells and cues from. Rankl increases the level of csrc protein, another marker molecule of osteoclast differentiation that is a widely expressed nonreceptor tyrosine kinase particularly abundant in platelets and neural tissues 26, 27 and osteoclasts 28, 29.
Osteoclasts were giant wine redpurple cells with more than 3 nuclei. Cgrp may regulate bone metabolism through stimulating. A, osteoclast formation in cocultures of mouse marrow cells with primary osteoblasts osteoblast or breast cancer cell lines in the presence or absence of 1. The most marked actin structure that distinguishes osteoclasts is the bone resorptive apparatus, the sealing zone. The mechanism of osteoclast differentiation induced by il. While osteoblasts and osteocytes are responsible for the production of bone, osteoclasts break it down. We examined the effects of ha at several molecular weights on osteoclast formation and function induced by rankl r eceptor a ctivator of n f. Osteoclastogenesis an overview sciencedirect topics. B, effect of breast cancer cells on osteoclast formation in cocultures of mouse marrow cells with primary osteoblasts.
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