title: Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification.
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.
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Morita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Fujita
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Ken
authors.initials: K
authors.lastname: Ninomiya
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Iwasaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Yagi
authors.forename: Hironari
authors.initials: H
authors.lastname: Takaishi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000111:Acetylcysteine