Inhibition of the classical NF-κB pathway prevents osteoclast bone-resorbing activity

Soysa, Niroshani Surangika; Alles, Neil; Shimokawa, Hitoyata; Jimi, Eijiro; Aoki, Kazuhiro; Ohya, Keiichi

doi:10.1007/s00774-008-0026-6

Cited by 43 publications

(41 citation statements)

References 37 publications

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“…S100A8 was shown to be an endogenous ligand for TLR-4, inducing intracellular translocation of myeloid differentiation factor 88 and activating interleukin-1 receptor-associated kinase and NF-B (12), the latter being crucial for osteoclast differentiation and function (47,48). Using TLR-4-deficient osteoclasts, we clearly demonstrated complete blockade of the S100A8-mediated increase in osteoclast formation and bone resorption.…”

Section: Discussionmentioning

confidence: 82%

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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Section: Discussionmentioning

confidence: 82%

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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show abstract

“…(23,54) Recent evidence, however, has shown that suppression of the NF-kB signaling pathway by the NBD peptide was able to prevent the antiosteoblastogenic activity of TNF-a in vitro, (55) suggesting that the NBD peptide could have an effect on bone formation and bone resorption in vivo. In this study, we found that the NBD peptide could prevent and rescue the reduced osteogenesis caused by LPS injection in vivo (Fig.…”

Section: Discussionmentioning

confidence: 99%

LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model

Tomomatsu

Aoki

Alles

et al. 2009

Journal of Bone and Mineral Research

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TNF-a is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF-a. Several lines of evidence show inhibition of osteoblastogenesis by TNF-a in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF-a. However, little is known about the inhibitory role of TNF-a in bone formation/ osteogenesis in vivo. The purpose of this study was to investigate the role of TNF-a in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF-a-deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF-a levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF-a signaling pathway by preventing transmission of the NF-kB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF-a might play a major role in LPS-induced inhibition of osteogenesis under inflammatory conditions.

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“…MMPs have been suggested to be involved in the pathogenesis of RA and OA through their ability to degrade proteoglycans [Flannery et al, 1992;Humbry et al, 1995]. NF-κB is essential for osteoclast formation and survival through the receptor activator of the nuclear factor kappa-B ligand (RANKL) pathway [Soysa et al, 2009]. Abnormal activation of NF-κB signalling in osteoclasts has been observed in osteolytic conditions, including arthritis, Paget's disease of bone, and periodontitis [Xu et al, 2009].…”

Section: Nf-κb In Ra Joint Destructionmentioning

confidence: 99%

“…Previous studies have shown that NF-κB controls osteoclast activation through RANKL signalling [Soysa & Alles, 2009], while inhibition or deletion of RANKL prevents bone destruction [Zwerina et al, 2004;Pettit et al, 2001]. The protective effect of MG132 may be a consequence of with interfering osteoclast activation through the RANKL signalling pathway that is under control of NF-κB, or by enhancing the osteoblast activity.…”

Section: Proteasome Inhibition and Joint Destructionmentioning

confidence: 99%

Proteasome Targeted Therapies in Rheumatoid Arthritis

Ahmed¹

2012

Rheumatoid Arthritis - Treatment

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Inhibition of the classical NF-κB pathway prevents osteoclast bone-resorbing activity

Cited by 43 publications

References 37 publications

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

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

LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model

Proteasome Targeted Therapies in Rheumatoid Arthritis

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