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J. Biol. Chem., Vol. 282, Issue 44, 32185-32192, November 2, 2007

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Mechanisms for Asporin Function and Regulation in Articular Cartilage^*

Masahiro Nakajima¹, Hideki Kizawa¹², Masao Saitoh, Ikuyo Kou, Kohei Miyazono, and Shiro Ikegawa³

From the Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan and the Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Osteoarthritis (OA), the most prevalent form of skeletal disease, represents a leading cause of disability following middle age. OA is characterized by the loss of articular cartilage; however, the details of its etiology and pathogenesis remain unclear. Recently, we demonstrated a genetic association between the cartilage extracellular matrix protein asporin and OA (Kizawa, H., Kou, I., Iida, A., Sudo, A., Miyamoto, Y., Fukuda, A., Mabuchi, A., Kotani, A., Kawakami, A., Yamamoto, S., Uchida, A., Nakamura, K., Notoya, K., Nakamura, Y., and Ikegawa, S. (2005) Nat. Genet. 37, 138-144). Furthermore, we showed that asporin binds to transforming growth factor- (TGF-), a key cytokine in OA pathogenesis, and inhibits TGF--induced chondrogenesis. To date, functional data for asporin have come primarily from mouse cell culture models of developing cartilage rather than from human articular cartilage cells, in which OA occurs. Here, we describe mechanisms for asporin function and regulation in human articular cartilage. Asporin blocks chondrogenesis and inhibits TGF-1-induced expression of matrix genes and the resulting chondrocyte phenotypes. Small interfering RNA-mediated knockdown of asporin increases the expression of cartilage marker genes and TGF-1; in turn, TGF-1 stimulates asporin expression in articular cartilage cells, suggesting that asporin and TGF-1 form a regulatory feedback loop. Asporin inhibits TGF-/Smad signaling upstream of TGF- type I receptor activation in vivo by co-localizing with TGF-1 on the cell surface and blocking its interaction with the TGF- type II receptor. Our results provide a basis for elucidating the role of asporin in the molecular pathogenesis of OA.

Received for publication, January 18, 2007 , and in revised form, September 6, 2007.

^* 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.

¹ Both authors contributed equally to this work.

² Present address: Frontier Research Laboratories, Pharmaceutical Research Div., Takeda Pharmaceutical Co., Osaka, Japan.

³ To whom correspondence should be addressed. Tel.: and Fax: 81-3-5449-5393; E-mail: sikegawa{at}ims.u-tokyo.ac.jp.

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