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Journal of Clinical Periodontology Apr 1986The osteoclast may play an important rŏle in the variable rate of osseous destruction seen in periodontitis. Current understanding of various aspects of the osteoclast... (Review)
Review
The osteoclast may play an important rŏle in the variable rate of osseous destruction seen in periodontitis. Current understanding of various aspects of the osteoclast may help explain this fact. This review paper will first look at two theories of cell origin of the osteoclast: the multipotential osteoprogenitor cell theory and the hemopoietic stem cell theory. Next, ultrastructural features characteristic to the cell such as the ruffled border, clear zone, and lysosomal system, will be discussed. Thirdly, current and proposed theories on the actual mechanism of bone degradation are considered. This includes the one-cell theory and the two-cell theory. Finally, elements which activate the osteoclast are enumerated and their delicate interplay is outlined. In the context of this information, pathways found in the periodontal lesion (microbial agents, inflammatory cells and their products) which attract and activate elements of the osteoclastic system are discussed.
Topics: Alveolar Process; Animals; Bacterial Physiological Phenomena; Bone Resorption; Collagen; Hematopoietic Stem Cells; Heparin; Humans; Monocytes; Neutrophils; Osteoblasts; Osteoclasts; Parathyroid Hormone; Periodontal Diseases; Periodontitis; Prostaglandins
PubMed: 3519690
DOI: 10.1111/j.1600-051x.1986.tb02220.x -
The Keio Journal of Medicine 2011Osteoclasts are multinuclear giant cells derived from osteoclast/macrophage/dendritic cell common progenitor cells. The most characteristic feature of osteoclasts is... (Review)
Review
Osteoclasts are multinuclear giant cells derived from osteoclast/macrophage/dendritic cell common progenitor cells. The most characteristic feature of osteoclasts is multinucleation resulting from cell-cell fusion of mononuclear osteoclasts. Osteoclast cell-cell fusion is considered essential for re-organization of the cytoskeleton, such as the actin-ring and ruffled boarder to seal the resorbing area and to secret protons, respectively, to resorb bone; the fusion process is thus critical for osteoclast function. Various molecules, such as E-cadherin and macrophage fusion receptor (MFR), have been identified as regulators of osteoclast or macrophage cell-cell fusion. Laboratory production of osteoclasts used to be performed in a co-culture of osteoclast progenitors with osteoblastic cells, but recent advances in the identification of nuclear factor of kappa B ligand (RANKL) enabled the isolation of osteoclast-specific molecules involving osteoclast cell-cell fusion and differentiation regulators from purified osteoclast mRNA, since osteoclasts can be formed without osteoblasts. The essential cell-cell fusion regulator, dendritic cell-specific transmembrane protein (DC-STAMP), was isolated by a cDNA subtractive screen between mononuclear macrophages and RANKL-induced multinuclear osteoclasts. The cell-cell fusion of osteoclasts and foreign body giant cells (FBGCs) was completely abrogated in DC-STAMP-deficient mice in vivo and in vitro. Bone resorbing activity was significantly reduced but was still detected in DC-STAMP-deficient osteoclasts. DC-STAMP expression is positively regulated by two transcriptional factors: nuclear factor of activated T cells 1 (NFATc1) and c-Fos, both of which are essential for osteoclast differentiation. Furthermore, a novel osteoclastogenesis-regulating pathway involving two transcriptional repressors [B cell lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein 1 (Blimp1)] under RANKL stimulation has been discovered. The expression of osteoclastic genes such as DC-STAMP, NFATc1, and Cathepsin K, as well as osteoclast differentiation, was inhibited by Bcl6. Bcl6-deficient mice showed enhanced osteoclastogenesis and reduced bone mass, whereas osteoclast-specific Blimp1-conditional knockout mice showed elevated Bcl6 expression, osteoclastic gene expression, and osteoclast differentiation and increased bone mass. In this review, recent advances in our understanding of the regulators of osteoclast differentiation and cell-cell fusion are discussed.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bone and Bones; Cell Differentiation; Cell Fusion; Homeostasis; Humans; Membrane Proteins; Osteoclasts; RANK Ligand
PubMed: 22200633
DOI: 10.2302/kjm.60.101 -
Experimental Hematology Aug 1999The osteoclast is a hematopoietic cell derived from CFU-GM and branches from the monocyte-macrophage lineage early during the differentiation process. The marrow... (Review)
Review
The osteoclast is a hematopoietic cell derived from CFU-GM and branches from the monocyte-macrophage lineage early during the differentiation process. The marrow microenvironment appears critical for osteoclast formation due to production of RANK ligand, a recently described osteoclast differentiation factor, by marrow stromal cells in response to a variety of osteotropic factors. In addition, factors such as osteoprotegerin, a newly described inhibitor of osteoclast formation, as well as secretory products produced by the osteoclast itself and other cells in the marrow enhance or inhibit osteoclast formation. The identification of the role of oncogenes such as c-fos and pp60 c-src in osteoclast differentiation and bone resorption have provided important insights in the regulation of normal osteoclast activity. Current research is beginning to delineate the signaling pathways involved in osteoclastic bone resorption and osteoclast formation in response to cytokines and hormones. The recent development of osteoclast cell lines may make it possible for major advances to our understanding of the biology of the osteoclast to be realized in the near future.
Topics: Animals; Apoptosis; Bone Marrow; Bone Resorption; CHO Cells; Carrier Proteins; Cell Differentiation; Cell Line; Cell Lineage; Cell Separation; Cricetinae; Cytokines; Glycoproteins; Hormones; Humans; Membrane Glycoproteins; Mice; Organ Culture Techniques; Osteoclasts; Osteoprotegerin; Proto-Oncogenes; RANK Ligand; Rats; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Signal Transduction; Stromal Cells; Transfection
PubMed: 10428500
DOI: 10.1016/s0301-472x(99)00061-2 -
Critical Reviews in Eukaryotic Gene... 1998The osteoclast is the primary bone-resorbing cell and is derived from the monocyte/macrophage lineage. Bipotent osteoclast precursors, which can form both osteoclasts... (Review)
Review
The osteoclast is the primary bone-resorbing cell and is derived from the monocyte/macrophage lineage. Bipotent osteoclast precursors, which can form both osteoclasts and monocyte-macrophages, proliferate and differentiate to become unipotent post-mitotic committed osteoclast precursors. These post-mitotic committed precursors fuse to form the multinucleated osteoclast, which is then activated to resorb bone. A variety of soluble and membrane-bound factors play a critical role in regulating osteoclast formation, including growth factors, systemic hormones, and cells in the marrow microenvironment, such as osteoblasts and marrow stromal cells. Cell-to-cell interactions are important in both the formation and activity of the osteoclast. Recent molecular biological studies have identified transcription factors, such as c-fos and PU.1, which are required for osteoclast differentiation. In this review, we discuss the phenotypic changes that are induced as the cells mature from bipotent early precursors to mature osteoclasts; factors that have been identified that are involved in this process; and the role of marrow stromal cells and osteoblasts in osteoclast differentiation.
Topics: Animals; Cell Differentiation; Humans; Osteoclasts
PubMed: 9673448
DOI: 10.1615/critreveukargeneexpr.v8.i1.10 -
Endocrine Reviews Aug 1996Much has been learned about the cell biology and molecular biology of the osteoclast in the last 5 yr. The osteoclast appears to be derived from CFU-GM, the committed... (Review)
Review
Much has been learned about the cell biology and molecular biology of the osteoclast in the last 5 yr. The osteoclast appears to be derived from CFU-GM, the committed monocyte-granulocyte precursor cell. This cell then differentiates into more committed precursors for the osteoclast. The role of the marrow microenvironment appears to be critical for murine osteoclast formation, although in human systems it appears to be nonessential but acts to enhance osteoclast formation and resorption. The osteoclast has been shown to be a secretory cell capable of producing both stimulators and inhibitors of osteoclast formation and resorption. The identification of the role of protooncogenes, such as c-fos and pp60c-src, in osteoclast differentiation and bone resorption has provided important insights into the regulation of normal osteoclast activity. Studies such as these should help us to dissect the pathophysiology of abnormal osteoclastic activity, such as seen in hypercalcemia of malignancy, osteopetrosis, and Paget's disease of bone. Future research is needed to further delineate the signaling pathways involved in osteoclastic bone resorption in response to cytokines and hormones, as well as to identify the molecular events required for commitment of multipotent precursors to the osteoclast lineage. Development of osteoclast cell lines may be possible and would greatly enhance our understanding of the biology of the osteoclast. Utilization of current model systems to examine the effects of cytokines and hormones on osteoclast precursors in vitro and in vivo and the ability to obtain large numbers of highly purified osteoclasts for production of osteoclast cDNA libraries should lead to important new discoveries in osteoclast biology.
Topics: Animals; Apoptosis; Bone Resorption; Cell Adhesion; Humans; Osteoclasts; Phenotype; Stem Cells
PubMed: 8854048
DOI: 10.1210/edrv-17-4-308 -
Histology and Histopathology Jan 2004The osteoclast is a bone-degrading polykaryon. Recent studies have clarified the differentiation of this cell and the biochemical mechanisms it uses to resorb bone. The... (Review)
Review
The osteoclast is a bone-degrading polykaryon. Recent studies have clarified the differentiation of this cell and the biochemical mechanisms it uses to resorb bone. The osteoclast derives from a monocyte/macrophage precursor. Osteoclast formation requires permissive concentrations of M-CSF and is driven by contact with mesenchymal cells in bone that bear the TNF-family ligand RANKL. Osteoclast precursors express RANK, and the interaction between RANKL and RANK (which is inhibited by OPG) is the major determinant of osteoclast formation. Hormones, such as PTH/PTHrP, glucocorticoids and 1,25(OH)2D3, and humoral factors, including TNFalpha, interleukin-1, TGFss and prostaglandins, influence osteoclast formation by altering expression of these molecular factors. TNFalpha, IL-6 and IL-11 have also been shown to promote osteoclast formation by RANKL-independent processes. RANKL-dependent/independent osteoclast formation is likely to play an important role in conditions where there is pathological bone resorption such as inflammatory arthritis and malignant bone resorption. Osteoclast functional defects cause sclerotic bone disorders, many of which have recently been identified as specific genetic defects. Osteoclasts express specialized proteins including a vacuolar-type H+-ATPase that drives HCl secretion for dissolution of bone mineral. One v-ATPase component, the 116 kD V0 subunit, has several isoforms. Only one isoform, TCIRG1, is up-regulated in osteoclasts. Defects in TCIRG1 are common causes of osteopetrosis. HCl secretion is dependent on chloride channels; a chloride channel homologue, CLCN7, is another common defect in osteopetrosis. Humans who are deficient in carbonic anhydrase II or who have defects in phagocytosis also have variable defects in bone remodelling. Organic bone matrix is degraded by thiol proteinases, principally cathepsin K, and abnormalities in cathepsin K cause another sclerotic bone disorder, pycnodysostosis. Thus, bone turnover in normal subjects depends on relative expression of key cytokines, and defects in osteoclastic turnover usually reflect defects in specific ion transporters or enzymes that play essential roles in bone degradation.
Topics: Animals; Bone Resorption; Calcitriol; Cell Differentiation; Cytokines; Glycoproteins; Humans; Macrophage Colony-Stimulating Factor; Models, Biological; Osteoclasts; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor
PubMed: 14702187
DOI: 10.14670/HH-19.189 -
Reviews in Endocrine & Metabolic... Jun 2006Osteoclasts are multinucleated cells derived from hematopoietic precursors that are primarily responsible for the degradation of mineralized bone during bone... (Review)
Review
Osteoclasts are multinucleated cells derived from hematopoietic precursors that are primarily responsible for the degradation of mineralized bone during bone development, homeostasis and repair. In various skeletal disorders such as osteoporosis, hypercalcemia of malignancy, tumor metastases and Paget's disease, bone resorption by osteoclasts exceeds bone formation by osteoblasts leading to decreased bone mass, skeletal fragility and bone fracture. The overall rate of osteoclastic bone resorption is regulated either at the level of differentiation of osteoclasts from their monocytic/macrophage precursor pool or through the regulation of key functional proteins whose specific activities in the mature osteoclast control its attachment, migration and resorption. Thus, reducing osteoclast numbers and/or decreasing the bone resorbing activity of osteoclasts are two common therapeutic approaches for the treatment of hyper-resorptive skeletal diseases. In this review, several of the key functional players involved in the regulation of osteoclast activity will be discussed.
Topics: Animals; Bone Resorption; Cell Adhesion; Humans; Models, Biological; Osteoclasts; Receptor Activator of Nuclear Factor-kappa B; Receptor, Macrophage Colony-Stimulating Factor; Receptors, Calcitonin; Signal Transduction
PubMed: 16951988
DOI: 10.1007/s11154-006-9009-x -
Journal of Cellular Biochemistry Dec 2007Osteoclasts are multinucleated cells that derive from hematopoietic progenitors in the bone marrow which also give rise to monocytes in peripheral blood, and to the... (Review)
Review
Osteoclasts are multinucleated cells that derive from hematopoietic progenitors in the bone marrow which also give rise to monocytes in peripheral blood, and to the various types of tissue macrophages. Osteoclasts are formed by the fusion of precursor cells. They function in bone resorption and are therefore critical for normal skeletal development (growth and modeling), for the maintenance of its integrity throughout life, and for calcium metabolism (remodeling). To resorb bone, the osteoclasts attach to the bone matrix, their cytoskeleton reorganizes, and they assume polarized morphology and form ruffled borders to secrete acid and collagenolytic enzymes and a sealing zone to isolate the resorption site. Identification of the osteoclastogenesis inducer, the receptor activator of nuclear factor-kappaB ligand (RANKL), its cognate receptor RANK, and its decoy receptor osteoprotegerin (OPG), has contributed enormously to the dramatic advance in our understanding of the molecular mechanisms involved in osteoclast differentiation and activity. This explosion in osteoclast biology is reflected by the large number of reviews which appeared during the last decade. Here I will summarize the "classical" issues (origin, differentiation, and activity) in a general manner, and will discuss an untouched issue (multinucleation) and a relatively novel aspect of osteoclast biology (osteoimmunology).
Topics: Animals; Bone Resorption; Cell Differentiation; Cell Nucleus; Hematopoietic System; Humans; Models, Biological; Osteoclasts
PubMed: 17955494
DOI: 10.1002/jcb.21553 -
Clinical Orthopaedics and Related... Sep 1993Osteoclasts develop from precursor cells of the monocyte series. However, specialized differentiation for efficient bone degradation separates the osteoclast from the... (Review)
Review
Osteoclasts develop from precursor cells of the monocyte series. However, specialized differentiation for efficient bone degradation separates the osteoclast from the macrophage. The physical reasons for these differences are emerging from the study of osteoclastic physiology and biochemistry. Key osteoclast specializations are multinucleation, formation of a tightly sealed extracellular compartment on bone, and high-capacity secretion of HCl and acid proteases into this extracellular site. Multinucleation increases efficiency of extracellular attachment processes. The attachment process is mediated by cell membrane integrins, and is sensitive to changes in intracellular or extracellular calcium. Acid production exploits carbonic acid as the source of acid and conjugate base equivalents, reflected in abundant osteoclastic carbonic anhydrase type II expression. Secretion of acid involves extremely high expression of vacuolar-type H(+)-ATPase and a chloride channel in the cell's specialized acid secreting organelle, the ruffled membrane, which is polarized to the osteoclast's bone attachment. Acid secretion is balanced by chloride-bicarbonate exchange in the cell's nonbone attached membranes; this functionally resembles the band 3 chloride-bicarbonate exchanger of the red cell carbon dioxide transport system. Bone collagen is degraded by acid proteases secreted into the acid degradation site via the mannose-6-phosphate receptor system, which is targeted to lysosomes in other cells. Functional deficits, as in osteopetrosis, may affect any of the elements involved in osteoclast differentiation. Furthermore, new antiosteoclastic therapeutic agents may inhibit osteoclast biochemistry intentionally, such as for the control of hypercalcemia of malignancy.
Topics: Bicarbonates; Biological Transport, Active; Bone Resorption; Calcium; Carbonic Acid; Cell Nucleus; Collagen; Humans; Hydrogen-Ion Concentration; Hydroxyapatites; Integrins; Osteoclasts; Sodium-Potassium-Exchanging ATPase
PubMed: 8395372
DOI: No ID Found -
Journal of Electron Microscopy 2003The mechanism by which bone collagen and other organic components are degraded by the osteoclast during osteoclastic bone resorption was unclear until the 1980s. Studies... (Review)
Review
The mechanism by which bone collagen and other organic components are degraded by the osteoclast during osteoclastic bone resorption was unclear until the 1980s. Studies conducted since the early 1990s have identified lysosomal proteases, mainly cathepsins that are active at low pH, involved in osteoclastic bone resorption. Several cathepsins, such as cathepsins C, D, B, E, G and L, were initially demonstrated to take part in the degradation of organic bone matrix in osteoclasts. Cathepsin K, which has high proteolytic activity and localizes primarily in osteoclasts, was discovered in 1995. This first tissue-specific cathepsin was associated with pycnodysostosis, a genetic disorder observable as an osteopetrotic phenotype in cathepsin K-deficient mice. Cystatin C, an endogenous inhibitor of cysteine proteases, regulates the activity of cathepsin K. However, detailed morphological observations suggest that the organic bone matrix is degraded by not only cathepsin K, but also by matrix metalloproteinases or other cathepsins. The osteoclast possesses a unique endocytotic/exocytotic structure and each cathepsin is specifically localized in the osteoclast, which implies that each cathepsin contributes cooperatively to the process of osteoclastic bone resorption. Further studies may clarify the regulation of cathepsin activities and the roles of cathepsins during bone remodelling.
Topics: Animals; Bone Matrix; Bone Resorption; Cathepsins; Humans; Mice; Osteoclasts; Rabbits; Rats
PubMed: 14756243
DOI: 10.1093/jmicro/52.6.551