Targeting Fcgr1 to repress FAPy-adenine-induced osteoporosis in osteosarcoma receiving chemotherapy

Résumé fourni par la source

Chemotherapy-induced bone loss in patients with osteosarcoma (OS) has attracted increasing attention worldwide. Previous studies have revealed the interactions between OS cells and osteoclasts via secretion of various cytokines. However, the specific impacts of chemically injured OS cells on osteoclast functions remain unknown. Untargeted metabolomics is a high-throughput analytical technique used to screen potential biomarkers and identify unknown metabolites in various biological samples. In this study, cisplatin (CDDP)-injured OS cell supernatant promoted the osteoclast differentiation of bone marrow macrophages (BMMs). Untargeted metabolomic analysis revealed the metabolic profile of injured OS cells, and FAPy-adenine (FA), which was upregulated by approximately 2000-fold, was identified in the supernatant. FA promoted the osteoclast differentiation of BMMs in a dose-dependent manner. RNA sequencing revealed increased Fc gamma receptor 1 (Fcgr1) expression levels in FA-treated BMMs. Fcgr1 overexpression promoted the osteoclast differentiation of BMMs and Cathepsin K expression, whereas its knockdown inhibited the pro-osteoclast differentiation effect of FA. Furthermore, FA accelerated osteoporosis progression in ovariectomy model rats. Upregulation of Fcgr1 levels promoted bone loss, whereas its silencing inhibited the bone loss induced by FA in ovariectomy model rats. Collectively, these findings suggest that FA released from CDDP-injured OS cells contributes to osteoporosis progression by upregulating Fcgr1 levels, providing new insights into chemotherapy-induced bone loss in patients with OS.

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