Genetic regulation of osteoclast development and function

Teitelbaum, Steven L.; Ross, F. Patrick

doi:10.1038/nrg1122

Cited by 1,508 publications

(1,275 citation statements)

References 121 publications

Supporting

Mentioning

1,240

Contrasting

Unclassified

Order By: Relevance

“…However, F-actin staining demonstrated that S100A8-stimulated osteoclasts contained significantly more actin rings per cell. Because bone resorption occurs only when a sealing zone is formed and the actin ring is present, creating the acidic environment crucial for cathepsin K activity (41)(42)(43), this suggests that S100A8 enhanced the bone resorptive capacity per osteoclast.…”

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

View full text Add to dashboard Cite

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

show abstract

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

View full text Add to dashboard Cite

show abstract

“…It interacts with the osteoclast cell surface receptor RANK, which in turn recruits TNFR-associated factors (TRAFs) (Darnay et al 1998;Wong et al 1998), and plays a crucial role in the osteoclast differentiation axis. The downstream intracellular signaling mediated by RANK in osteoclast progenitor cells includes TRAF6-dependent activation of nuclear factor (NF)-jB via the inhibitor of NF-jB (IjB) kinase (IKK)-IjB pathway and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK) (Boyle et al 2003;Lerner 2004;Teitelbaum and Ross 2003). In addition, immunoreceptor tyrosine-based activation motif-mediated costimulatory signals have been shown to be required for expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), the transcription factor believed to be crucial for osteoclast differentiation (Koga et al 2004;Mocasi et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of luteolin on osteoclast differentiation and function

et al. 2009

View full text Add to dashboard Cite

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.

show abstract

“…This is necessary because unlike a macrophage or a neutrophil, osteoclasts do not degrade their targets internally in lysosomes. The osteoclast must create a seal at the bone surface (described in greater detail later), and form an "extracellular lysosome" (Teitelbaum et al, 2003). As shown in figure 4, while the area of the cross section taken rests the same proportionally in several nonfused cells and a fused multikaryon, the volume increases.…”

Section: Multinucleationmentioning

confidence: 99%

“…The high amount of acid secreted by the osteoclast is necessary to dissolve the hydroxyapatite that makes up the majority of the bone structure. It's also necessary for the acidic hydrolases, particularly cathepsin K, to become active and degrade the remaining organic matrix (Teitelbaum et al, 2003). The motor powering acid secretion in osteoclasts are the vacuolar (v-) type H+-ATPases.…”

Section: Ion Channels and Transportersmentioning

confidence: 99%