Department of Orthopedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China.
School of Medicine, Southeast University, Nanjing, People's Republic of China.
J Cell Mol Med. 2024 Oct;28(20):e70127. doi: 10.1111/jcmm.70127.
Diabetic calcific tendinopathy is the leading cause of chronic pain, mobility restriction, and tendon rupture in patients with diabetes. Tendon stem/progenitor cells (TSPCs) have been implicated in the development of diabetic calcified tendinopathy, but the molecular mechanisms remain unclear. This study found that diabetic tendons have a hyperoxic environment, characterized by increased oxygen delivery channels and carriers. In hyperoxic environment, TSPCs showed enhanced osteogenic differentiation and increased levels of reactive oxygen species (ROS). Additionally, hypoxia-inducible factor-1a (HIF-1a), a protein involved in regulating cellular responses to hyperoxia, was decreased in TSPCs by the ubiquitin-proteasome system. By intervening with antioxidant N-acetyl-L-cysteine (NAC) and overexpressing HIF-1a, we discovered that blocking the ROS/HIF-1a signalling axis significantly inhibited the osteogenic differentiation ability of TSPCs. Animal experiments further confirmed that hyperoxic environment could cause calcification in the Achilles tendon tissue of rats, while NAC intervention prevented calcification. These findings demonstrate that hyperoxia in diabetic tendons promotes osteogenic differentiation of TSPCs through the ROS/HIF-1a signalling axis. This study provides a new theoretical basis and research target for preventing and treating diabetic calcified tendinopathy.
糖尿病性钙化性肌腱病是糖尿病患者慢性疼痛、活动受限和肌腱断裂的主要原因。肌腱干/祖细胞（TSPCs）被认为与糖尿病性钙化性肌腱病的发展有关，但分子机制尚不清楚。本研究发现，糖尿病肌腱处于一种富氧环境中，其特征是增加了氧气输送通道和载体。在富氧环境中，TSPCs 表现出增强的成骨分化和增加的活性氧（ROS）水平。此外，缺氧诱导因子-1a（HIF-1a），一种参与调节细胞对缺氧反应的蛋白质，通过泛素-蛋白酶体系统在 TSPCs 中减少。通过干预抗氧化剂 N-乙酰-L-半胱氨酸（NAC）和过表达 HIF-1a，我们发现阻断 ROS/HIF-1a 信号通路可显著抑制 TSPCs 的成骨分化能力。动物实验进一步证实，富氧环境可导致大鼠跟腱组织钙化，而 NAC 干预可预防钙化。这些发现表明，糖尿病肌腱中的富氧环境通过 ROS/HIF-1a 信号通路促进 TSPCs 的成骨分化。本研究为预防和治疗糖尿病性钙化性肌腱病提供了新的理论基础和研究靶点。
