HOXA7 Impairs Osteogenic Differentiation via p38/JNK Signaling: Implications for Osteoporosis.

OBJECTIVE: To elucidate the role and mechanism of HOXA7 in osteoporosis (OP), with the goal of informing future research directions in OP. METHODS: We assessed HOXA7 gene and protein expression; the effect of HOXA7 on osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs); and proliferation, apoptosis, and autophagy in MC3T3-E1 cells. We also evaluated p38 MAPK/JNK pathway-associated proteins in hBMSCs and MC3T3-E1 cells. Cells were transfected with si-HOXA7 and cultured with or without the JNK inhibitor SP600125 or the p38 inhibitor SB203580, after which cell viability, apoptosis, and autophagy were re-assessed. RESULTS: HOXA7 overexpression inhibited osteogenic differentiation of hBMSCs, reduced OPG, OPN, and RUNX2 expression in hBMSCs, and decreased proliferation while promoting apoptosis in MC3T3-E1 cells. In vitro, HOXA7 modulated autophagy markers in MC3T3-E1 cells. Phosphorylated JNK and p38 (p-JNK, p-p38) were increased in hBMSCs following osteogenic induction, whereas HOXA7 upregulation significantly suppressed p-JNK and p-p38 in MC3T3-E1 cells. SP600125 and SB203580 attenuated the effects of HOXA7 silencing on proliferation, apoptosis, and autophagy in MC3T3-E1 cells. CONCLUSION: HOXA7 reduces osteogenesis and osteoblast proliferation and promotes osteoblast apoptosis via the p38 MAPK/JNK pathway, suggesting potential therapeutic avenues against OP.