FSTL1 promotes osteoclast differentiation and Accelerates periprosthetic osteolysis via PP2A Cα-Mediated activation of the JNK signaling pathway.

Periprosthetic osteolysis (PPO) is a common cause of arthroplasty failure, characterized by chronic inflammation and osteoclast differentiation, ultimately necessitating revision surgery. Follistatin-like 1 (FSTL1) is a critical modulator of inflammation and has an important function in different inflammatory disorders, including osteoarthritis and rheumatoid arthritis. This research examines the function of FSTL1 in PPO and elucidates the underlying mechanisms. In human aseptic loosening periprosthetic interface membranes and titanium (Ti) nanoparticle-induced calvarial osteolysis models, FSTL1 expression was markedly elevated. The administration of recombinant FSTL1 (rFSTL1) to calvariae significantly exacerbated Ti nanoparticle-induced bone resorption at osteolytic sites and increased both osteoclastogenesis and pro-inflammatory factor expression. However, the knockdown of FSTL1 using adeno-associated virus (AAV) effectively mitigated calvarial osteolysis and decreased both osteoclastogenesis and pro-inflammatory factor expression. Mechanistically, FSTL1 facilitates osteoclast differentiation and bone resorption through the upregulation of protein phosphatase 2A C subunit alpha (PP2A Cα) expression, which enhances the RANKL-induced activation of the JNK signaling pathway, thereby increasing the expression of downstream transcription factors cellular proto-oncogene Fos (c-Fos) and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). Furthermore, FSTL1 intensifies the inflammatory response at osteolytic sites, also contributing to the progression of osteolysis. Our findings indicate that FSTL1 may represent a promising therapeutic target for the treatment of periprosthetic osteolysis.