The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20062525
The Journal of Experimental Medicine, Vol. 204, No. 7, 1613-1623
The Rockefeller University Press, 0022-1007 $30.00
© Morita et al.
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ARTICLE

 Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification

Kozo Morita1,2, Takeshi Miyamoto1,2,3, Nobuyuki Fujita1,2, Yoshiaki Kubota1, Keisuke Ito1, Keiyo Takubo1, Kana Miyamoto1, Ken Ninomiya1,2, Toru Suzuki1,2, Ryotaro Iwasaki1,4, Mitsuru Yagi1,2, Hironari Takaishi2, Yoshiaki Toyama2, and Toshio Suda1

1 Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, 2 Department of Orthopedic Surgery, 3 Department of Musculoskeletal Reconstruction and Regeneration Surgery, and 4 Department of Dentistry and Oral Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan

CORRESPONDENCE Takeshi Miyamoto: miyamoto{at}sc.itc.keio.ac.jp OR Toshio Suda: sudato{at}sc.itc.keio.ac.jp

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.

Abbreviations used: ATM, ataxia telangiectasia mutated; DCF-DA, dichlorodihydrofluorescein diacetate; ERK, extracellular signal-regulated kinase; Eth, ethidium; H&E, hematoxylin and eosin; JNK, c-Jun-N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK activating kinase; MMP, matrix metalloproteinase; NAC, N-acetyl cysteine; PECAM, platelet-endothelial cell adhesion molecule; ROS, reactive oxygen species.

K. Morita and T. Miyamoto contributed equally to this work.


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