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

IntroductionOsteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass, deterioration of bone microarchitecture, and decreased bone strength, resulting in increased fragility and fracture risk 1,2 .OP is a growing public health burden worldwide, with particularly high impact in the Asia-Pacific region due to its large and aging population 3,4 .Globally, osteoporotic fractures are estimated to occur every 3 seconds, causing substantial patient morbidity and imposing significant economic costs 5 . Despite available therapies, important limitations remain.There is an urgent need to improve understanding of OP risk factors, identify new therapeutic targets, and strengthen targeted prevention and treatment strategies.Homeobox (HOX) genes encode a family of transcription factors that are aberrantly expressed in various tumors.In humans, 39 HOX genes are organized into four clusters-HOXA, HOXB, HOXC, and HOXD 6 .These clusters occupy defined chromosomal loci; for example, the HOXA cluster resides at 7p15.3.In osteoblastogenesis, the HOXA cluster is of particular interest, and many HOXA-encoded proteins contribute to normal skeletal development 7 .Overexpression of HOXA7 (also known historically as HOX1.1) in transgenic animals provokes perinatal Abstract 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.