Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered the core pathological characteristic of
steroid-associated
osteonecrosis of the femoral head (SONFH).
N6-Methyladenosine (m6A) is the most common type of
RNA modification in eukaryotic cells and participates in various physiological and
pathological processes. However, the relationship between
m6A modification and SONFH has not been reported. In the present study, we aimed to explore the roles of
m6A modifications and
methyltransferase METTL14 in SONFH. Our results showed that the
m6A levels were down-regulated in femoral head tissues and BMSCs from SONFH patients, and this effect was attributed to the reduction of METTL14. Furthermore, METTL14 overexpression in BMSCs from SONFH patients enhanced cell proliferation and osteogenic differentiation. We further identified PTPN6 as the downstream target of METTL14 by
mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt signaling pathway, and this effect was caused by the interaction of PTPN6 and GSK-3β. In conclusion, we elucidated the functional roles of METTL14 and
m6A methylation in SONFH BMSCs and identified a novel
RNA regulatory mechanism, providing a potential therapeutic target for SONFH.