IGF2BP2 Drives Subchondral Bone Damage in Temporomandibular Joint Osteoarthritis through PPARγ/C-FOS-regulated Dual Pathways: NFATC1 Signaling and ATG16L2-Mediated Autophagy.

Overactivated osteoclastogenesis leading to abnormal subchondral bone loss is the main feature of temporomandibular joint osteoarthritis (TMJOA) deterioration. The role of N6-methyladenosine (m6A) in osteoclast-mediated subchondral bone loss in TMJOA remains unknown. Here, we found that an m6A reader IGF2BP2 was essential for mature osteoclasts induction. In TMJ tissues of TMJOA patients, the expression of IGF2BP2 was increased. Moreover, IGF2BP2 was augmented in subchondral bone of monosodium iodoacetate (MIA)-induced TMJOA mice. Igf2bp2 deficiency attenuated MIA-induced subchondral bone loss and suppressed osteoclast function. Mechanistically, IGF2BP2 directly stabilized Pparg and Fos mRNA to enhance the NFATC1 signaling, thereby inducing osteoclast maturation. Furthermore, the stabilized PPARγ promoted the transcription of Fos, resulting in a further amplified signaling of NFATC1. In Igf2bp2-deficient cells, overexpression of PPARγ and C-FOS rescued the function of osteoclasts through restoring reduced levels of NFATC1. On the other hand, IGF2BP2/PPARγ/C-FOS axis facilitated the formation of osteoclasts by restoring the inhibited autophagy levels through the downregulation of ATG16L2. Using an IGF2BP2 inhibitor CWI1-2 hindered osteoclast formation and mitigated synovial inflammation, cartilage degeneration, and bone destruction in MIA-induced TMJOA mice. In summary, IGF2BP2 may be as a novel regulator of osteoclastogenesis of TMJOA pathogenesis, and aggravates TMJOA pathology via stabilizing Pparg and Fos mRNA, which promoting NFATC1-mediated osteoclast signaling and ATG16L2-mediated autophagy.