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J. Biol. Chem., Vol. 282, Issue 44, 32193-32199, November 2, 2007

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Expression and Regulation of the Osteoarthritis-associated Protein Asporin^*

From the Laboratory for Bone and Joint Disease, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

Asporin (ASPN) is a small leucine-rich proteoglycan that is involved in pathological processes of osteoarthritis. Previously, we showed that asporin can inhibit transforming growth factor-1 (TGF-1)-mediated expression of cartilage matrix genes and chondrogenesis in vitro (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). However, details about regulation of asporin itself are not yet known. Here, we examined ASPN expression in skeletal tissue and potential regulation of ASPN by TGF-. In situ hybridization revealed the presence of ASPN mRNA in the perichondrium/periosteum of long bones, but its absence in articular cartilage and growth plates. Immunohistochemical analysis also showed ASPN protein expression predominantly in the perichondrium/periosteum. TGF-1 induced endogenous ASPN mRNA expression over time in vitro, and this induction was suppressed by the TGF- type I receptor kinase inhibitor SB431542. Inhibition of Smad3 significantly reduced TGF-1-induced ASPN expression, whereas overexpression of Smad3 augmented the induction. Characterization of the human ASPN promoter region revealed a region from -126 to -82 that is sufficient for full promoter activity; however, TGF-1 failed to increase activity through the ASPN promoter. Our findings indicate that TGF-1 induces ASPN through Smad3 but that this induction is indirect.

Received for publication, July 30, 2007 , and in revised form, September 4, 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 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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