Enhancing osteogenic differentiation of diabetic tendon stem/progenitor cells through hyperoxia: Unveiling ROS/HIF-1α signalling axis

J Cell Mol Med. 2024 Oct;28(20):e70127. doi: 10.1111/jcmm.70127.

Abstract

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.

Keywords: Hyperoxia; N‐acetyl‐L‐cysteine; diabetic calcified tendinopathy; osteogenic differentiation; reactive oxygen species; tendon stem/progenitor cells.

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Cell Differentiation*
  • Diabetes Mellitus, Experimental* / metabolism
  • Diabetes Mellitus, Experimental* / pathology
  • Hyperoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Male
  • Osteogenesis*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species* / metabolism
  • Signal Transduction*
  • Stem Cells* / cytology
  • Stem Cells* / metabolism
  • Tendons* / metabolism
  • Tendons* / pathology

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • Acetylcysteine