Periprosthetic osteolysis is mediated by the m6A-dependent regulation of CEMIP via YTHDF2

Wear particle-induced periprosthetic osteolysis (PPO) represents the primary reason for implant failure following joint replacement, driven by macrophage polarization and excessive osteoclastogenesis. While cell migration inducing hyaluronidase 1 (CEMIP) has been implicated in inflammation and bone metabolism, its role in wear particle-induced PPO remains unexplored. Here, we discover that CEMIP expression was upregulated in Ti particle-induced calvarial osteolysis model. Functional studies revealed that CEMIP knockdown could attenuate Ti particle-triggered bone resorption via suppressing macrophage M1 polarization, promoting M2 polarization, and inhibiting osteoclast differentiation, as evidenced by reduced M1 markers, increased M2 markers, decreased inflammatory cytokines, and osteoclast-specific gene expression. In vitro, CEMIP silencing suppressed IFNγ-induced M1 polarization, enhanced IL-4-induced M2 polarization, and RANKL/M-CSF-triggered osteoclastogenesis in bone marrow-derived macrophages (BMDMs). Mechanistically, wear particle exposure decreases N6-methyladenosine (m6A) modification of CEMIP mRNA, impairing m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2)-mediated recognition and subsequent mRNA decay, thereby stabilizing CEMIP transcripts and enhancing their expression. Furthermore, CEMIP knockdown counteracted the enhancement of M1 macrophage polarization and osteoclast differentiation resulting from YTHDF2 silencing. Collectively, these findings highlight the critical role of the YTHDF2/CEMIP axis in regulating macrophage polarization and osteoclast differentiation, thus offering a promising therapeutic target for wear particle-induced PPO.

CEMIP; Macrophage polarization; Osteoclastogenesis; Periprosthetic osteolysis; YTHDF2.