Background/Purpose: Progressive loss of joint structure is a hallmark of rheumatoid arthritis (RA). TNFα has been shown to promote the destruction of bone by increasing the number of bone-resorbing osteoclasts and decreasing the number of bone-forming osteoblasts. The Wnt-Inhibitor sclerostin negatively regulates osteoblast differentiation and the disruption of this endogenous inhibitor increases the ability of Wnts to stabilize β-catenin and stimulate osteogenesis. Since it has been shown that sclerostin is upregulated in response to TNFα, we studied its role in inflammatory arthritis using the hTNF transgenic (hTNFtg) mice model of RA.

Methods: Sclerostin expression was assessed by immunohistochemistry, Western-blot-analysis, and RT‑PCR. The localisation of β-catenin was determined by immunfluorescence staining. Western-blot-analysis was used to evaluate p38-MAPK phosphorylation. Sclerostin knockout (SOST^-/-) mice were crossed with hTNFtg mice to generate TNFα overexpressing mice that lack sclerostin (SOST^-/-hTNFtg). Clinical disease severity, bone erosion, cartilage destruction and synovial inflammation in SOST^-/-hTNFtg and hTNFtg mice were evaluated by histomorphometric, x-ray and micro-CT analysis. hTNFtg mice were treated with blocking antibodies against murine sclerostin or control-vehicle.

Results: Immunhistological staining revealed high expression of sclerostin in synovial tissue of hTNFtg ankle joints, especially in infiltrating synovial-like fibroblasts (SF). Only negligible staining was observed in wildtype animals. In vitro, hTNFtg SF expressed sclerostin whereas wildtype did not. Unexpectedly, radiographic, microCT and histopatological examination of hind paw joints of SOST^-/-hTNFtg mice demonstrated that the loss of sclerostin dramatically accelerated joint damage in this mouse model of RA. SOST^-/-hTNFtg mice displayed significantly more synovial hyperplasia, proteoglycan loss and bone erosion compared to hTNFtg mice. Moreover, injection of a neutralizing antibody to murine sclerostin in hTNFtg mice did not improve clinical signs of arthritis and but led to elevated inflammation as well as bone erosion. In vitro, upon stimulation of hTNFtg and SOST^-/-hTNFtg SF with recombinant Wnt3a, β-catenin translocated to the nucleus, but this was not affected by loss of sclerostin. Of note, recombinant sclerostin was able to inhibit the TNFα induced p38-MAPK activation of wildtype SF.

Conclusion: Since p38-MAPK signalling specifically regulates inflammation induced bone loss, our data strongly suggest a protective function of sclerostin against TNFα-mediated joint destruction by inhibition of TNFα induced p38-activation in synovial fibroblasts. The blockade of inflammatory cytokine action proposes a complete novel function of sclerostin.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/sclerostin-protects-against-inflammatory-bone-loss-by-regulating-tnfalpha-mediated-p38-mapkinase-activation/