Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification

Kozo Morita, Takeshi Miyamoto, Nobuyuki Fujita, Yoshiaki Kubota, Keisuke Ito, Keiyo Takubo, Kana Miyamoto, Ken Ninomiya, Toru Suzuki, Ryotaro Iwasaki, Mitsuru Yagi, Hironari Takaishi, Yoshiaki Toyama, Toshio Suda

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121 Citations (Scopus)

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. JEM

Original languageEnglish
Pages (from-to)1613-1623
Number of pages11
JournalJournal of Experimental Medicine
Volume204
Issue number7
DOIs
Publication statusPublished - 2007 Jul 9

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Morita, K., Miyamoto, T., Fujita, N., Kubota, Y., Ito, K., Takubo, K., Miyamoto, K., Ninomiya, K., Suzuki, T., Iwasaki, R., Yagi, M., Takaishi, H., Toyama, Y., & Suda, T. (2007). Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification. Journal of Experimental Medicine, 204(7), 1613-1623. https://doi.org/10.1084/jem.20062525