gms | German Medical Science

Introduction: Sclerostin is a wnt inhibitor and has anti-anabolic effects on bone formation, by negatively regulating osteoblast differentiation. Therefore, pharmacological inhibition of sclerostin is a promising target to treat osteoporosis. Surprisingly, the loss of sclerostin in a TNFα-dependent arthritis mouse model (hTNFtg) caused a deterioration of disease severity, displayed by enhanced bone erosion and an elevated number of osteoclasts within the arthritic joints1. Our aim was to investigate direct and indirect effects of sclerostin on osteoclast differentiation and bone erosion in arthritis.

Methods: Sclerostin knockout (sost-/-) mice were crossbred with hTNFtg mice to obtain sost-/-hTNFtg mice, from which synovial fibroblasts (FLS) were isolated. Osteoclast differentiation was analysed using co-cultures of FLS with fluorescent protein (GFP+) bone marrow-derived macrophages (BMM) or mono-cultures with wt or b-cateninD/D BMM. Levels of receptor activator of NF-kB ligand (RANKL), osteoprotegerin (OPG) and macrophage colony stimulating factor (M-CSF) expression were measured by ELISA. Luciferase Assays were used to evaluate wnt activity in supernatants of FLS.

Results: Co-cultures of sost-/-hTNFtg FLS and GFP+ BMM showed increased osteoclast formation in comparison to hTNFtg FLS at unaltered levels of RANKL, OPG and MCSF. Treatment of wt BMM with conditioned media from sost-/-hTNFtg FLS showed an increase in osteoclast formation compared to hTNFtg FLS, pointing to a secreted factor that is affecting osteoclastogenesis. Analysis of hTNFtg FLS-derived supernatants displayed, that the loss of sclerostin increased the ability to stimulate canonical wnt signalling. Inhibition of wnt signalling either in FLS or BMM by blocking wnt secretion of FLS or using b-cateninD/D BMM abolished the stimulatory effects on osteoclast formation, suggesting that in the crosstalk of FLS and BMM increased wnt signalling causes enhanced osteoclast differentiation. In addition, treatment of wt BMM with recombinant sclerostin led to the inhibition of osteoclast differentiation indicating that sclerostin directly acts as an inhibitor of osteoclast differentiation.

Conclusion: Sclerostin appears to have a protective function in TNF⍺-mediated inflammatory bone destruction by regulating wnt signaling in BMM in a paracrine and autocrine manner, thereby inhibiting osteoclast differentiation.

Disclosures: None declared