Wu Meng, Li Huilan, Sun Xiaoting, Zhong Rongrong, Cai Linli, Chen Ruibo, Madeniyet Madiya, Ren Kana, Peng Zhen, Yang Yujie, Chen Weiqin, Tu Yanling, Lai Miaoxin, Deng Jinxiu, Wu Yuting, Zhao Shumin, Ruan Qingyan, Rao Mei, Xie Sisi, Ye Ying, Wan Jianxin
Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Department of Nephrology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
JCI Insight. 2025 Jan 30;10(5):e184468. doi: 10.1172/jci.insight.184468.
Renal osteodystrophy is commonly seen in patients with chronic kidney disease (CKD) due to disrupted mineral homeostasis. Given the impaired renal function in these patients, common antiresorptive agents, including bisphosphonates, must be used with caution or even contraindicated. Therefore, an alternative therapy without renal burden to combat renal osteodystrophy is urgently needed. Here, we report that clinically relevant aerobic exercise significantly prevents high-turnover renal osteodystrophy in CKD mice and patients with CKD without compromising renal function. Mechanistically, 4-week aerobic exercise in CKD mice increased expression of skeletal muscle PPARγ coactivator-1α (PGC-1α) and circulating irisin. Both exercise and irisin administration significantly activated osteoblasts, but not osteoclasts, via integrin αvβ5, thereby conferring bone quality benefits. Removal of irisin-influenced thermogenic adipose tissues or genetic ablation of uncoupling protein 1 did not alter the irisin-conferred antiosteodystrophy effect. Importantly, in a pilot clinical study, 12-week aerobic exercise in patients with high-grade CKD significantly increased circulating irisin and prevented osteodystrophy progression, without detectable renal burden. The combination of irisin and current antiresorptive agents effectively rescued renal osteodystrophy in mice. Our work provides mechanistic insights into the role of exercise and irisin in renal osteodystrophy, and it highlights a clinically relevant, low-cost, kidney-friendly therapy for patients with this devastating disease.
肾性骨营养不良常见于慢性肾脏病（CKD）患者，原因是矿物质稳态被破坏。鉴于这些患者肾功能受损，常用的抗吸收剂，包括双膦酸盐，必须谨慎使用甚至禁用。因此，迫切需要一种无肾脏负担的替代疗法来对抗肾性骨营养不良。在此，我们报告临床相关的有氧运动能显著预防CKD小鼠和CKD患者的高转换型肾性骨营养不良，且不损害肾功能。从机制上讲，CKD小鼠进行4周有氧运动可增加骨骼肌过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）的表达和循环鸢尾素水平。运动和给予鸢尾素均通过整合素αvβ5显著激活成骨细胞，而非破骨细胞，从而改善骨质量。去除受鸢尾素影响的产热脂肪组织或对解偶联蛋白1进行基因敲除，并未改变鸢尾素赋予的抗骨营养不良作用。重要的是，在一项初步临床研究中，重度CKD患者进行12周有氧运动可显著增加循环鸢尾素水平并预防骨营养不良进展，且未检测到肾脏负担。鸢尾素与目前的抗吸收剂联合使用可有效挽救小鼠的肾性骨营养不良。我们的工作为运动和鸢尾素在肾性骨营养不良中的作用提供了机制性见解，并突出了一种针对这种毁灭性疾病患者的临床相关、低成本、肾脏友好型治疗方法。
