FSCN1 induces subchondral bone sclerosis in osteoarthritis via modulating actin cytoskeleton dynamics and YAP signaling.

Abstract

BACKGROUND: Subchondral bone is a dynamic tissue maintained by bone remodeling and responded rapidly to mechanical loading, which is strongly associated with cartilage degradation in osteoarthritis (OA), but the underlying mechanisms of which is still blurring. METHODS: Experimental OA mice models were generated by mechanical overload with 60 cycles of 14 N axial compressive loads twice a week or anterior cruciate ligament transection surgery. FSCN1 expression was evaluated in subchondral bone from experimental OA mice and human OA. Mice with FSCN1 conditional knockout in pre-osteoblasts were generated, and adeno-associated virus expressing FSCN1 was injected intra-articularly in mice. Therapeutic efficacy of FSCN1 inhibitor NP-G2-044 was determined in OA mice. RESULTS: Increased FSCN1 expression was positively associated with osteogenesis and subchondral bone sclerosis induced by mechanical loading. Deletion of FSCN1 in pre-osteoblasts delays osteogenesis and prevents abnormal subchondral bone sclerosis, whereas overexpression of FSCN1 exacerbates this. Under the stimulation of mechanical stress, Ras homologue gene family member A in osteoblasts competitively binds with protein kinase C to FSCN1, thereby inhibiting FSCN1 phosphorylation and promoting cytoskeleton formation, thereby activating Hippo/YAP signaling to increase metabolic activity of osteoblasts. These abnormal osteoblasts secrete more osteogenesis proteins, including osteopontin, leading to subchondral bone sclerosis and cartilage erosion, thus aggravating the progression of OA. Furthermore, we confirmed that the inhibitor of FSCN1, NP-G2-044 effectively attenuates subchondral bone sclerosis and OA progression in mice. CONCLUSIONS: This study suggests that FSCN1 is a key factor in the relationship between mechanical stress, actin cytoskeleton dynamic, subchondral bone sclerosis and OA pathology. Targeting FSCN1 represents a promising pharmacological approach for OA therapy.