Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.

双磷酸盐相关性颌骨坏死 (BRONJ) 的特点是口面部骨髓基质细胞 (BMSC) 成骨分化受损。 Corin 最近被证明是骨骼发育和骨科疾病的关键调节剂。然而，corin 在 BRONJ 相关 BMSC 功能障碍中的作用仍不清楚。我们小组的 m6A 表观转录组微阵列研究表明，在口面部 BMSC 成骨分化过程中， CORIN基因显着上调且 m6A 高甲基化。 Corin敲低抑制BMSCs成骨分化，而corin过表达或可溶性corin (sCorin)则发挥促进作用。此外，corin 表达受到双磷酸盐 (BP) 的负调节。 Corin 过表达或 sCorin 可逆转 BP 受损的 BMSC 分化能力。从机制上讲，我们发现 corin 敲低/过度表达 BMSC 和 sCorin 刺激下的 BMSC 中 phos-ERK 的表达发生改变。 PD98059（一种选择性 ERK 抑制剂）可阻断 corin 介导的促进作用。针对corin在成骨分化过程中的高甲基化水平，我们应用了非选择性m6A甲基化酶抑制剂环亮氨酸，它也阻断了corin介导的促进作用。此外，我们证明 METTL7A 调节 corin m6A 修饰并逆转 BP 受损的 BMSC 功能，表明 METTL7A 调节 corin 表达，从而有助于口面部 BMSC 的分化能力。总之，我们的研究表明，corin 可逆转 BP 诱导的 BMSC 功能障碍，而 METTL7A 介导的 corin m6A 修饰是 corin 通过 ERK 途径促进成骨分化的基础。我们希望这能为 BRONJ 未来的临床治疗带来新的见解。