Betaine Alleviates Bisphosphonate-Related Osteonecrosis of the Jaw by Rescuing BMSCs Function in an m6A-METTL3-Dependent Manner.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the side effects of bisphosphonate (BP) administration. Despite some preventive measures having been suggested, a definitive and effective treatment strategy for BRONJ remains to be established. Recent evidence has indicated that BPs dramatically impair the function of orofacial bone marrow stromal cells (BMSCs), which may contribute to the development of osteonecrosis. Thus, we hypothesized that recovery-impaired function of BMSCs at lesion sites could be beneficial in treating BRONJ. N6-methyladenosine (m6A) modification is the most common epigenetic modification and has been demonstrated to play a vital role in the modulation of BMSCs' function. We detected the role of m6A modification in regulating the function of orofacial BMSCs under BP stimulation, and found that BPs led to a reduction in the global m6A methylation level, SAM level, and METTL3 expression in BMSCs during the osteogenic differentiation period. Meanwhile, betaine, a methyl group donor, effectively reversed the BP-decreased global m6A methylation level and SAM level in BMSCs, as well as rescuing the differentiation ability of impaired BMSCs. In the last part, we built a BRONJ rat model and supplemented rats with betaine via drinking water. The results showed that betaine successfully attenuated bone lesions and promoted wound healing in BP-injected rats, thereby providing new insight into future clinical treatment for BRONJ.