Follistatin-Like Protein 1 (FSTL1) Modulates Bone Remodeling and Attenuates Bone Loss in a Mouse Model of Postmenopausal Osteoporosis

Abstract This study systematically delineates the expression dynamics of follistatin-like protein 1 (FSTL1) in postmenopausal osteoporosis (PMOP) and elucidates its role in skeletal homeostasis. Integrated analyses of clinical serum samples and the GTEx database revealed a pronounced reduction in circulating FSTL1 levels in PMOP patients. In vivo, Fstl1+/– ovariectomised mice displayed exacerbated bone loss—evidenced by diminished bone mineral density and trabecular volume—together with impaired osteoblastic activity and heightened osteoclast activation. Complementary in vitro experiments showed that FSTL1 over-expression markedly enhanced osteogenic differentiation, as reflected by increased alkaline phosphatase activity and matrix mineralisation, whereas FSTL1 knockdown produced the opposite effect. Conversely, FSTL1 over-expression suppressed osteoclastogenesis, while its silencing facilitated the formation of tartrate-resistant acid phosphatase–positive osteoclasts. Therapeutic administration of recombinant FSTL1 protein in vivo significantly attenuated OVX-induced bone loss and improved trabecular architecture, stimulated osteoblast differentiation, and curtailed osteoclast function. Collectively, these findings position FSTL1 as a down-regulated mediator in PMOP that modulates bone remodelling by simultaneously promoting osteogenesis and restraining osteoclastogenesis, supporting a potential association of FSTL1 with PMOP and its possible relevance as a biomarker and therapeutic target.