Follistatin-like protein 1 (FSTL1) modulates bone remodeling and attenuates bone loss in a mouse model of postmenopausal osteoporosis.

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(+/-) ovariectomized mice displayed exacerbated bone loss-evidenced by diminished BMD 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 mineralization, 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 remodeling 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.