Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 Drives Subchondral Bone Damage in Temporomandibular Joint Osteoarthritis through Peroxisome Proliferator-Activated Receptor γ/C-FOS-Regulated Dual Pathways: Nuclear Factor of Activated T Cells 1 Signaling and Autophagy-Related 16-Like 2-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 in osteoclast-mediated subchondral bone loss in TMJOA remains unknown. Here, we found that an N6-methyladenosine reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was essential for mature osteoclast induction. In TMJ tissues of patients with TMJOA, 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 nuclear factor of activated T cells 1 (NFATC1) signaling, thereby inducing osteoclast maturation. Furthermore, the stabilized peroxisome proliferator-activated receptor γ (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, the IGF2BP2/PPARγ/C-FOS axis facilitated the formation of osteoclasts by restoring the inhibited autophagy levels through the down-regulation of autophagy-related 16-like 2. 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 a novel regulator of osteoclastogenesis of TMJOA pathogenesis, and aggravates TMJOA pathology via stabilizing Pparg and Fos mRNA, which promotes NFATC1-mediated osteoclast signaling and autophagy-related 16-like 2-mediated autophagy.