An Yuanming, Zheng Lizhen, Zhang Shi'an, Zhang Haozhi, Zhang Yuantao, Shao Hongwei, Tong Wenxue, Chen Ziyi, Yao Hao, Wen Zhenkang, Xu Shunxiang, Li Ye, Tian Qinyu, Cheng Liming, Sun Wei, Qin Ling, Xu Jiankun
Musculoskeletal Research Laboratory, Centre for Musculoskeletal Degeneration & Regeneration, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chines University of Hong Kong, Hong Kong Special Administrative Region of China; The Sir Yue-Kong Pao Cancer Centre, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
Musculoskeletal Research Laboratory, Centre for Musculoskeletal Degeneration & Regeneration, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chines University of Hong Kong, Hong Kong Special Administrative Region of China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation (InnoHK), Chinese Academy of Sciences, Hong Kong Special Administrative Region of China.
Biomaterials. 2025 Dec;323:123428. doi: 10.1016/j.biomaterials.2025.123428. Epub 2025 May 19.
Steroid-associated osteonecrosis (SAON) remains a challenging clinical condition as there are few effective preventive measures. This study investigates the effects of hydrogen (H) administrated via saturated hydrogen-rich water (HRW) in mice received high dose of glucocorticoids (for inducing SAON model). Here we find that HRW treatment significantly reduces osteocyte apoptosis, improves deteriorated trabecular architecture, increases osteoblast numbers and the bone formation, while decreases osteoclast numbers and the bone resorption. Additionally, HRW-treated mice exhibit improved serum lipid profiles, including decreased levels of low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (T-CHO), as well as reduced lipid accumulation. HRW treatment also enhances blood perfusion and increases formation of type H vessels in SAON mice. We further demonstrate that HRW shifts the polarization of macrophages from M1 to M2 phenotype and suppresses inflammatory marker TNF-α. RNA sequencing data and subsequent validation reveal that HRW upregulates ACOD1 mRNA and protein levels in bone tissues. The protective effects of HRW are mimicked by supplementation with the itaconate derivative dimethyl itaconate in a dose-dependent manner, highlighting the importance of the ACOD1-itaconate pathway in the prevention of SAON by HRW. These findings indicate that HRW ameliorates SAON by modulating the ACOD1-itaconate pathway, presenting a novel avenue for the cost-effective prevention of osteonecrosis.
类固醇相关的骨坏死（SAON）仍然是一种具有挑战性的临床病症，因为有效的预防措施很少。本研究调查了通过富氢饱和水（HRW）给予氢气（H）对接受高剂量糖皮质激素（用于诱导SAON模型）的小鼠的影响。在这里，我们发现HRW治疗可显著减少骨细胞凋亡，改善恶化的小梁结构，增加成骨细胞数量和骨形成，同时减少破骨细胞数量和骨吸收。此外，接受HRW治疗的小鼠的血脂谱得到改善，包括低密度脂蛋白（LDL）、甘油三酯（TG）和总胆固醇（T-CHO）水平降低，以及脂质积累减少。HRW治疗还可增强SAON小鼠的血液灌注并增加H型血管的形成。我们进一步证明，HRW可使巨噬细胞的极化从M1表型转变为M2表型，并抑制炎症标志物肿瘤坏死因子-α（TNF-α）。RNA测序数据及后续验证表明，HRW可上调骨组织中ACOD1的mRNA和蛋白水平。衣康酸衍生物衣康酸二甲酯以剂量依赖性方式补充可模拟HRW的保护作用，突出了ACOD1-衣康酸途径在HRW预防SAON中的重要性。这些发现表明，HRW通过调节ACOD1-衣康酸途径改善SAON，为骨坏死的经济有效预防提供了一条新途径。
