Novel roles of S100A4 in the pathogenesis of rheumatoid arthritis and bone metastasis

Abstract

S100A4 is a member of the S100 calcium-binding protein family which has been implicated in various pathological conditions including cancers and arthritis, which often accompany bone destruction. Recently, the roles of S100A4 in progression of cancer metastasis and rheumatoid arthritis (RA) have been demonstrated in several studies. However, how S100A4 affects the bone microenvironment during pathogenesis of RA and bone metastasis has not been elucidated. Based on the results of ELISA, S100A4 was highly expressed in synovial fluid of RA patients. Interestingly, in silico analyses demonstrated that the expression of S100A4 was maintained in RA patients even after TNF-alpha inhibitor treatment. Moreover, breast cancer patients with bone metastases expressed elevated levels of S100A4 by searching publicly available data sets. In line with that finding, in vivo selection of bone metastasized prostate and breast cancer in athymic mice showed increased expression of S100A4. In this study, I demonstrated in vivo and in vitro that the extracellular S100A4 proteins decreased the bone volume of mice calvariae, resulting from enhancement of osteoclastogenesis and interruption of osteoblast function. I observed that the receptor for advanced glycation end products (RAGE), a direct binding target of S100A4, mediated osteoclastogenesis via activation of classical NF-B signaling pathways upon S100A4 treatment. Moreover, the extracellular S100A4 inhibited the mineralization by osteoblasts by activating the NF-B pathway. Additionally, synovial fibroblasts from RA patients expressed high levels of receptor activator of nuclear factor B ligand (RANKL), a potent cytokine of osteoclastogenesis, upon S100A4 treatment. These results demonstrated the bone destructive effect of extracellular S100A4 in bone homeostasis and suggested a novel therapeutic target to cure bone metastasis and RA.