Chen Fang, Gu Meizhen, Xu Hongming, Zhou Shasha, Shen Zilu, Li Xiaoyan, Dong Liangchao, Li Pin
Department of Otolaryngology-Head and Neck Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China.
Department of Endocrinology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China.
J Transl Med. 2025 Jul 28;23(1):845. doi: 10.1186/s12967-025-06849-w.
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.
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.
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.
Our findings reveal an epigenetic mechanism underlying CIH-induced long bone dysplasia and highlight T0070907 as a promising targeted therapeutic agent.
阻塞性睡眠呼吸暂停（OSA）引起的慢性间歇性缺氧（CIH）常导致严重并发症。然而，CIH对骨骼生长发育的不良影响往往被忽视。
使用OxyCycler A84系统进行CIH干预，每天8小时（上午8:00至下午4:00），持续4周。测量体长和股骨长度，并进行显微CT、组织学分析和酶联免疫吸附测定（ELISA）以评估股骨发育。进行代谢组学、单细胞转录组学、蛋白质免疫印迹和染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）分析，以探索CIH诱导长骨生长抑制的潜在机制。每两天腹腔注射T0070907（0.5mg/kg），以研究其在CIH条件下对长骨生长的影响。
在此，我们表明长骨发育期间的CIH刺激显著抑制长骨生长。多组学分析显示，CIH诱导骨髓间充质干细胞（BM-MSCs）进行无氧糖酵解，促进脂肪生成分化，并降低其成骨分化能力。机制研究表明，CIH诱导的乳酸积累增强了BM-MSCs中PPARγ启动子上组蛋白H3赖氨酸18（H3K18）的乳酰化，导致PPARγ的转录激活，从而使BM-MSCs的脂肪生成和成骨分化之间失衡。PPARγ抑制剂T0070907可部分挽救CIH诱导的长骨发育障碍。
我们的研究结果揭示了CIH诱导长骨发育异常的表观遗传机制，并突出了T0070907作为一种有前景的靶向治疗药物。
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