Chronic intermittent hypoxia impairs BM-MSC osteogenesis and long bone growth through regulating histone lactylation

Abstract

BACKGROUND: Chronic intermittent hypoxia (CIH) caused by OSA often results in serious complications. However, the adverse effects of CIH on bone growth and development are often overlooked. METHODS: CIH intervention was conducted using an OxyCycler model A84 system for 8 h per day (from 8:00 a.m. to 4:00 p.m.) over a period of 4 weeks. Body and femur lengths were measured, and micro-CT, histological analysis, and ELISA were performed to evaluate femoral development. Metabolomic, single-cell transcriptomic, Western blot, and ChIP‒qPCR analyses were conducted to explore the potential mechanisms underlying CIH-induced inhibition of long bone growth. T0070907 was administered intraperitoneally (0.5 mg/kg) every two days to investigate its effect on long bone growth under CIH conditions. RESULTS: Here, we showed that CIH stimulation during long bone development significantly inhibited long bone growth. Multiomics analysis revealed that CIH induces anaerobic glycolysis in bone marrow mesenchymal stem cells (BM-MSCs), promotes adipogenic differentiation, and reduces their osteogenic differentiation capacity. Mechanistic studies demonstrated that CIH-induced lactate accumulation enhances lactylation at histone H3 lysine 18 (H3K18) on the PPARγ promoter in BM-MSCs, leading to the transcriptional activation of PPARγ and a consequent imbalance between the adipogenic and osteogenic differentiation of BM-MSCs. The PPARγ inhibitor T0070907 could partially rescue long bone developmental disorders induced by CIH. CONCLUSIONS: Our findings reveal an epigenetic mechanism underlying CIH-induced long bone dysplasia and highlight T0070907 as a promising targeted therapeutic agent.