Secretory phosphoprotein 1 secreted by fibroblast-like synoviocytes promotes osteoclasts formation via PI3K/AKT signaling in collagen-induced arthritis

Abstract

Synovial tissue hyperplasia is a major cause of bone damage in rheumatoid arthritis (RA). Over-proliferation and secretion of cytokines of fibroblast-like synoviocytes (FLSs) are key contributors to bone damage in the joint microenvironment. Therefore, inhibition of FLSs-mediated bone damage is of great significance in RA patients. The aim of this study was to investigate the molecular mechanisms by which FLSs-mediated bone damage in the joint microenvironment. The results of whole transcriptome sequencing showed that Spp1 gene expression was significantly upregulated in collagen-induced arthritis FLSs compared to Normal FLSs. KEGG enrichment analysis revealed up-regulated Spp1 gene expression, associated with PI3K/AKT signaling. Animal and cellular experiments were designed to validate and explore the results of sequencing. Briefly, the data demonstrated secretory phosphoprotein 1 (SPP1) (encoded by Spp1 gene) secreted by FLSs promotes osteoclasts differentiation in vivo and in vitro and exacerbates articular bone damage in collagen-induced arthritis mice. Interestingly, SPP1 secreted by FLSs does not affect its own proliferation and apoptosis. The results of co-culture of FLSs with bone marrow-derived monocytes indicated the level of SPP1 secreted by FLSs positively correlates with the frequency of p-PI3K+PI3K+ osteoclasts, whereas not with the frequency of p-AKT+AKT+ osteoclasts. This may suggest that SPP1 secreted by FLSs acts directly on PI3K while indirectly on AKT. Together, the results revealed SPP1 secreted by FLSs promotes osteoclasts formation via PI3K/AKT signaling in collagen-induced arthritis. Regulation of Spp1 gene expression in FLSs may be a potential approach to treat RA bone damage in the joint microenvironment.