The identification of rankrankl signaling as the main signal regulating osteoclast differentiation was a major breakthrough in the bone biology field. Using the present protocol, a large number of giant osteoclasts were seen on day 6. 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. Breast cancer cells interact with osteoblasts to support. The present study also indicates that ocif acts as a naturally occurring decoy receptor for odf in inhibiting signal transduction in human osteoclast formation. Osteoclasts are multinucleated cells of hematopoietic origin which are unique in their ability to resorb bone. Mar 09, 2016 while osteoblasts and osteocytes are responsible for the production of bone, osteoclasts break it down. Regulation of the differentiation and function of osteoclasts. Evidence in facour of this comes from studies of osteoclast generation in co. This is an attempt to give a birdseyeview of the players in osteoclast formation and differentiation in a brief and concise manner. Benjamin ma, md, professor, chief, sports medicine and shoulder service, ucsf department of orthopaedic surgery, san francisco, ca.
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. In addition to the calcineurinnfatc1 axis, calcium signaling activates the calmodulin. Molecular understanding of osteoclast differentiation and. These culture systems have made it possible to investigate each step of osteoclast development and function separately. The osteoclast is the giant cell of bone phylogenically evolved to resorb the bone matrix. Loss of csrc results in formation of ocl that cannot. 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. Stem cells, leading to cells forming laying down new bone tissue. Osteoclastogenesis inhibitory factor ocif, also called opg is a secreted tnf receptor, which acts as a decoy receptor for odf. The physiology and pathophysiology of the osteoclast.
The osteoclasts, multinucleared cells originating from the hematopoietic monocytemacrophage lineage, are responsible for bone resorption. In addition remarkable discoveries have been made to broaden the knowledge of the molecular mechanisms of osteoclast formation and differentiation. We developed a coculture system with mouse spleen cells and osteoblastic cells to examine the role of osteoblasts in osteoclast formation. A ranklbased osteoclast culture assay of mouse bone. Osteoclast progenitor cells are recruited from haematopoietic compartments, and then proliferate and differentiate toward mature osteoclasts. 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. Such advances in the understanding of the molecular mechanism of osteoclast differentiation are expected to lead to novel therapeutic approaches to bone diseases. Nov 08, 2012 osteoclast formation and differentiation. As the sole bone resorptive cell type, osteoclasts possess a remarkably dynamic actin cytoskeleton that drives their function in this enterprise. Osteoclasts are multinucleated cells of monocytemacrophage origin that degrade bone matrix. The inhibition of osteoclast differentiation is via negative regulation of rankl and.
Mechanisms of mechanically induced osteoclastogenesis. Review article regulation of osteoclast differentiation by. Many other cytokines impact osteoclast formation by inducing rankl and mcsf, while. Hence, a better understanding of the pathways leading to osteoclast differentiation is vital in successfully managing such diseases. Finally, osteoblastderived vegf stimulated osteoclast formation in the final remodeling phase of the repair process. Pdf osteoclasts are multinucleated cells of hematopoietic origin which are unique in their ability to resorb bone. Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. Importantly, osteoblast numbers and bone formation were reduced, supporting that osteoclast tgf. Osteoclastic definition of osteoclastic by the free. Odf is responsible for inducing not only differentiation, but also activation of osteoclasts. Collagen triple helix repeat containing 1, a novel secreted protein in. Osteoclast derivation from mouse bone marrow protocol.
It has been our experience that the in vitro cultivation of osteoclasts from bone marrow is. 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. 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 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. It has been our experience that the in vitro cultivation of osteoclasts from bone marrow is largely dependent on seeding density. 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. Osteoclast differentiation factor odf is a key mediator of pthinduced bone resorption. Hscs undergo differentiation into oc precursors depending on the presence of pu. Schematic representation of oc differentiation and activation. Osteoclast article about osteoclast by the free dictionary. Osteoblast lineage cells, whose mature form is responsible for bone formation, also regulate the differentiation of osteoclast precursors into osteoclasts. 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. The most marked actin structure that distinguishes osteoclasts is the bone resorptive apparatus, the sealing zone. 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.
Macrophage colonystimulating factor mcsf induces myeloid precursors to differentiate to osteoclast precursors that express rank receptor activator of nf. Mcsf is a key player in promoting the proliferation and survival of osteoclast precursor cells. Our understanding of the differentiation and function of osteoclasts has advanced deeply with advances in science. The differentiation of oc precursors into mononuclear and multinucleated ocs is further modulated by rankl and mcsf signaling. Osteoclasts were giant wine redpurple cells with more than 3 nuclei. Osteoclast differentiation factor odf induces osteoclast. 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. The molecular understanding of osteoclast differentiation. Cgrp may regulate bone metabolism through stimulating. 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. Odf, together with colonystimulating factor1, is both necessary and sufficient to induce osteoclastogenesis. 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.
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 molecular basis of osteoclast differentiation and. The mechanism of osteoclast differentiation induced by il. Osteoclast formation and activity increase in response to inactivity and low calcium blood levels, which causes bones to become thinner and weaker. B and trem2 triggering receptor expressed by myeloid cells2 receptors. Bone remodeling, nci thesaurus osteoclasts are derived through the fusion of cells of the monocytemacrophage lineage. 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. 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. Osteoclastogenesis an overview sciencedirect topics. Osteoclasts are generated from myeloid progenitors.
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. However, the rate of osteoclast formation, and thus bone resorption, outpaces. The coordinated development and function of boneforming osteoblasts and boneresorbing osteoclasts cells is critical for the maintenance of skeletal integrity and calcium homeostasis. Successful osteoclast formation was confirmed by trap staining figure 2a. Osteoclast differentiation an overview sciencedirect. Molecular mechanisms regulating the differentiation and function of osteoclasts have been elucidated since the previous edition of this book. Osteoclast differentiation and function is under the control of neighboring immature osteoblasts or bone lining cells of the endosteum or periosteum 15. Osteoclast differentiation 103 ferentiation through induction of a second transcription factor nfatc1, which is critical for ocl differentiation. Osteoclasts are large cells, derived from stem cells in the bone marrow that give rise to. Two essential cytokines macrophage colonystimulating factor and the receptor activator of nuclear factor. 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. Of note is the stable gene upregulation induced by mcsf and three waves of. Osteoclasts are generated from myeloid progenitors through a progression that involves the fusion of mononuclear precursor cells.
Medcram medical lectures explained clearly 185,844 views. 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. B, effect of breast cancer cells on osteoclast formation in cocultures of mouse marrow cells with primary osteoblasts. 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. Of note is the stable gene upregulation induced by mcsf and three waves of gene regulation induced by rankl.
B ligand regulate osteoclast differentiation and activity. A large multinucleate cell found in growing bone that resorbs bony tissue, as in the formation of canals and cavities. While osteoblasts and osteocytes are responsible for the production of bone, osteoclasts break it down. Osteoclastlike cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. 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.
When mouse spleen cells and osteoblastic cells isolated from fetal mouse calvariae were cocultured in the presence of 10 nm l. On the other hand, a specific promoter of osteoclast differentiation does seem likely to be a product of cells of the stromalosteoblast series. For osteoclasts to be formed, both hematopoietic progenitor cells and cues from. The role of nfat in osteoclast formation takayanagi. Osteoclast regulation of bone formation mayo clinic. Transcriptional program of mouse osteoclast differentiation. Inhibiting its action blocks the resorptive effects of pth 33. 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, osteoclast formation in cocultures of mouse marrow cells with primary osteoblasts osteoblast or breast cancer cell lines in the presence or absence of 1. Opg is a secreted tnfrrelated protein that regulates bone density and bone mass in animals22,23, and upon. 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. Osteoclast differentiation an overview sciencedirect topics.
Osteoclast, large multinucleated cell responsible for the dissolution and absorption of bone. Mechanisms by which cells of the osteoblast lineage. The osteoclasts are the mediators of the continuous destruction of bone. Osteoclastogenesis is mainly regulated by signaling pathways activated by rank and immune receptors, whose ligands are expressed on the surface of osteoblasts. It is a large cell with separately identifiable, multiple nuclei. A ranklbased osteoclast culture assay of mouse bone marrow. The endosteal surface had some areas of new bone formation but numerous. Osteoclastogenesis is mainly regulated by signaling pathways activated by rank and immune receptors, whose ligands are. 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. Mechanisms involved in enhancement of osteoclast formation.
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