Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification

J Exp Med. 2007 Jul 9;204(7):1613-23. doi: 10.1084/jem.20062525. Epub 2007 Jun 18.

Abstract

Chondrocyte hypertrophy during endochondral ossification is a well-controlled process in which proliferating chondrocytes stop proliferating and differentiate into hypertrophic chondrocytes, which then undergo apoptosis. Chondrocyte hypertrophy induces angiogenesis and mineralization. This step is crucial for the longitudinal growth and development of long bones, but what triggers the process is unknown. Reactive oxygen species (ROS) have been implicated in cellular damage; however, the physiological role of ROS in chondrogenesis is not well characterized. We demonstrate that increasing ROS levels induce chondrocyte hypertrophy. Elevated ROS levels are detected in hypertrophic chondrocytes. In vivo and in vitro treatment with N-acetyl cysteine, which enhances endogenous antioxidant levels and protects cells from oxidative stress, inhibits chondrocyte hypertrophy. In ataxia telangiectasia mutated (Atm)-deficient (Atm(-/-)) mice, ROS levels were elevated in chondrocytes of growth plates, accompanied by a proliferation defect and stimulation of chondrocyte hypertrophy. Decreased proliferation and excessive hypertrophy in Atm(-/-) mice were also rescued by antioxidant treatment. These findings indicate that ROS levels regulate inhibition of proliferation and modulate initiation of the hypertrophic changes in chondrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Antioxidants / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Calcification, Physiologic / drug effects
  • Calcification, Physiologic / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Division
  • Cell Line
  • Chondrocytes / cytology*
  • Chondrocytes / drug effects
  • Chondrocytes / pathology
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Hypertrophy
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic / drug effects
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Reactive Oxygen Species / metabolism
  • Reactive Oxygen Species / pharmacology*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics

Substances

  • Antioxidants
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • Acetylcysteine