Bone Resorption by Osteoclasts

Teitelbaum, Steven L.

doi:10.1126/science.289.5484.1504

Cited by 3,478 publications

(2,931 citation statements)

References 55 publications

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“…This hypothesis is supported by several observations: first, proinflammatory cytokines, such as TNF␣, IL-1, and IL-6, are found to be systemically up-regulated in RA patients (41)(42)(43). Second, proinflammatory cytokines such as TNF and IL-1 induce a molecule that is pivotally involved in the activation and differentiation of osteoclasts; that molecule is RANKL, which engages its receptor RANK on osteoclast precursor cells (24)(25)(26)(27). Third, serum parameters of bone metabolism reflect an increased bone resorption as the major cause for RA-associated generalized bone loss (14,(19)(20)(21).…”

Section: Discussionmentioning

confidence: 79%

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Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Schett¹,

Redlich²,

Hayer³

et al. 2003

Arthritis & Rheumatism

139

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Objective. To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.Methods. We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.Results. Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (؊37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (؊85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNFmediated bone loss by increasing BMD (؉89%) and bone volume (؉647%). Most strikingly, formation of primary spongiosa was dramatically increased (؉563%) in hTNFtg mice after OPG treatment. Osteoclastcovered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1␤ (IL-1␤), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.Conclusion. OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.

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Section: Discussionmentioning

confidence: 79%

“…RANKL stimulates osteoclast differentiation and activation by binding to its receptor RANK on osteoclast precursor cells and mature osteoclasts, thus shifting the balance to an excess of bone resorption (26,27). Osteoprotegerin (OPG) is a naturally occurring decoy receptor of RANKL and blocks its action by preventing RANKL-RANK interaction (28).…”

mentioning

confidence: 99%

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Schett¹,

Redlich²,

Hayer³

et al. 2003

Arthritis & Rheumatism

139

View full text Add to dashboard Cite

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“…Attachment of osteoclasts to the bone matrix induces their activation and leads to reorganization of the actin cytoskeleton, formation of sealing zones, and a polarized ruffled membrane juxtaposed to bone. The formation of actin rings is highly characteristic for osteoclasts and is related to their capacity to resorb bone (24,35). It was previously demonstrated that S100A9, in complex with S100A8, promoted polymerization of microtubules, and that S100A9-deficient granulocytes contained significantly less polymerized tubulin (36).…”

Section: Discussionmentioning

confidence: 99%

S100A8 enhances osteoclastic bone resorption in vitro through activation of Toll‐like receptor 4: Implications for bone destruction in murine antigen‐induced arthritis

Grevers¹,

Vries²,

Vogl³

et al. 2011

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis, which is associated with elevated levels of S100A8 and S100A9, is characterized by severe bone erosions caused by enhanced osteoclast formation and activity. The aim of the present study was to investigate the role of S100A8 and S100A9 in osteoclastic bone destruction in murine antigen-induced arthritis (AIA).Methods. Bone destruction was analyzed in the arthritic knee joints of S100A9-deficient mice in which S100A8 protein expression was also lacking, and in wild-type (WT) controls. Osteoclast precursors from S100A9-deficient and WT mice were differentiated into osteoclasts in vitro. Additionally, precursors were stimulated with S100A8, S100A9, or S100A8/A9 during osteoclastogenesis. Receptor involvement was investigated using an anti-receptor for advanced glycation end products (anti-RAGE)-blocking antibody, soluble RAGE, or Toll-like receptor 4 (TLR-4)-deficient osteoclast precursors. The formation of osteoclasts and actin rings, the regulation of osteoclast markers, and bone resorption were analyzed.Results. Bone erosions and cathepsin K staining were significantly suppressed in S100A9-deficient mice after AIA induction. However, osteoclast precursors from S100A9-deficient mice developed normally into functional osteoclasts, which excludes a role for intrinsic S100A8/A9. In contrast to the results observed with S100A9 and S100A8/A9, the addition of S100A8 during osteoclastogenesis resulted in stimulation of osteoclast formation in conjunction with enhanced actin ring formation and increased bone resorption. Analysis of the putative receptor for S100A8 in osteoclastogenesis revealed that osteoclast differentiation and function could not be inhibited by blocking RAGE, whereas the increase in osteoclast numbers and enhanced bone resorption were completely abrogated using TLR-4-deficient osteoclast precursors.Conclusion. These results demonstrate that S100A8 stimulated osteoclast formation and activity and suggest that both S100A8 and TLR-4 are important factors in mediating osteoclastic bone destruction in experimental arthritis.Bone erosions are an important hallmark of rheumatoid arthritis (RA) and typically result from enhanced formation and activity of osteoclasts in affected joints. Osteoclasts originate from hematopoietic precursors of the monocyte/macrophage lineage that differentiate into multinucleated osteoclasts under the

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“…Osteoclasts originate from hematopoietic precursor cells of the phagocyte lineage and differentiate into multinucleated cells by the fusion of mononuclear progenitors (Suda et al 1991). This process consists of multiple steps, including differentiation of osteoclast precursors into mononuclear osteoclasts, fusion of mononuclear preosteoclasts into mature multinucleated osteoclasts and activation of osteoclasts to resorb bone (Boyle et al 2003;Rodan and Martin 2000;Teitlebaum 2000;Chambers 2000). Therefore, natural compounds that specifically inhibit these steps could be developed as anti-resorptive drugs for the treatment of metabolic bone disorders characterized by excessive osteoclastic bone resorption.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of luteolin on osteoclast differentiation and function

et al. 2009

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Osteoclasts are multinucleated cells that play a crucial role in bone resorption, and are formed by the fusion of mononuclear osteoclasts derived from osteoclast precursors of the macrophage lineage. Compounds that specifically target functional osteoclasts would be ideal candidates for anti-resorptive agents for clinical applications. In the present study, we investigated the effects of luteolin, a flavonoid, on the regulation of receptor activator of nuclear factorjB ligand (RANKL)-induced osteoclastogenesis, functions and signaling pathway. Addition of luteolin to a coculture system of mouse bone marrow cells and ST2 cells in the presence of 10 -8 M 1a,25(OH) 2 D 3 caused significant inhibition of osteoclastogenesis. Luteolin had no effects on the 1a,25(OH) 2 D 3 -induced expressions of RANKL, osteoprotegerin and macrophage colony-stimulating factor mRNAs. Next, we examined the direct effects of luteolin on osteoclast precursors using bone marrow macrophages and RAW264.7 cells. Luteolin completely inhibited RANKL-induced osteoclast formation. Moreover, luteolin inhibited the bone resorption by mature osteoclasts accompanied by the disruption of their actin rings, and these effects were reversely induced by the disruption of the actin rings in mature osteoclasts. Finally, we found that luteolin inhibited RANKLinduced osteoclastogenesis through the suppression of ATF2, downstream of p38 MAPK and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) expression, respectively. Taken together, the present results indicate that naturally occurring luteolin has inhibitory activities toward both osteoclast differentiation and functions through inhibition of RANKL-induced signaling pathway as well as actin ring disruption, respectively.

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Bone Resorption by Osteoclasts

Cited by 3,478 publications

References 55 publications

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

S100A8 enhances osteoclastic bone resorption in vitro through activation of Toll‐like receptor 4: Implications for bone destruction in murine antigen‐induced arthritis

Inhibitory effect of luteolin on osteoclast differentiation and function

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