Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 Drives Subchondral Bone Damage in Temporomandibular Joint Osteoarthritis through Peroxisome Proliferator-Activated Receptor γ/Cellular FOS Proto-oncogene–Regulated Dual Pathways

Abstract

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, it was 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 cellular FOS proto-oncogene (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. 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, which aggravates TMJOA pathology via stabilizing Pparg and Fos mRNA, thereby promoting NFATC1-mediated osteoclast signaling and autophagy-related 16-like 2–mediated autophagy.