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J. Biol. Chem., Vol. 283, Issue 40, 27154-27164, October 3, 2008

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Smad7 Inhibits Chondrocyte Differentiation at Multiple Steps during Endochondral Bone Formation and Down-regulates p38 MAPK Pathways^*

Takao Iwai, Junko Murai, Hideki Yoshikawa, and Noriyuki Tsumaki¹

From the Departments of Bone and Cartilage Biology and Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Bone morphogenetic proteins (BMPs) play critical roles at various stages in endochondral bone formation. In vitro studies have demonstrated that Smad7 regulates transforming growth factor-β and BMP signals by inhibiting Smad pathways in chondrocytes. However, the in vivo roles of Smad7 during cartilage development are unknown. To investigate distinct effects of Smad7 at different stages during chondrocyte differentiation, we generated a series of conditional transgenic mice that overexpress Smad7 in chondrocytes at various steps of differentiation by using the Cre/loxP system. We generated Col11a2-lacZ^floxed-Smad7 transgenic mice and mated them with three types of Cre transgenic mice to obtain Smad7^Prx1, Smad7^11Enh, and Smad7^11Prom conditional transgenic mice. Smad7^Prx1 mice overexpressing Smad7 in condensing mesenchymal cells showed disturbed mesenchymal condensation associated with decreased Sox9 expression, leading to poor cartilage formation. Smad7^11Enh mice overexpressing Smad7 in round chondrocytes showed decreased chondrocyte proliferation rates. Smad7^11Prom mice overexpressing Smad7 in flat chondrocytes showed inhibited maturation of chondrocytes toward hypertrophy. Micromass culture of mesenchymal cells showed that BMP-induced cartilaginous nodule formation was down-regulated by overexpression of Smad7, but not Smad6. Overexpression of Smad7, but not Smad6, down-regulated the phosphorylation of p38 MAPKs. Our data provide in vivo evidence for distinct effects of Smad7 at different stages during chondrocyte differentiation and suggest that Smad7 in prechondrogenic cells inhibits chondrocyte differentiation possibly by down-regulating BMP-activated p38 MAPK pathways.

Received for publication, February 13, 2008 , and in revised form, July 17, 2008.

^* This work was supported in part by Scientific Research Grants 18390415 and 19659378 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by Health and Labor Sciences of Japan research grants. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed. Fax: 81-6-6879-3559; E-mail: ntsumaki{at}dbcb.med.osaka-u.ac.jp.

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