Lysyl Oxidase Binds Transforming Growth Factor-β and Regulates Its Signaling via Amine Oxidase Activity^*

Phimon Atsawasuwan, Yoshiyuki Mochida, Michitsuna Katafuchi, Masaru Kaku, Keith S. K. Fong, Katalin Csiszar, , and Mitsuo Yamauchi¹

Dental Research Center, University of North Carolina at Chapel Hill, North Carolina 27599-7455 and Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii-96822

Abstract: Lysyl oxidase (LOX), an amine oxidase critical for the initiation of collagen and elastin cross-linking, has recently been shown to regulate cellular activities possibly by modulating the functions of growth factors. In this study, we investigated the interaction between LOX and transforming growth factor-β1 (TGF-β1), a potent growth factor abundant in bone, the effect of LOX on TGF-β1 signaling, and its potential mechanism. The specific binding between mature LOX and mature TGF-β1 was demonstrated by immunoprecipitation and glutathione S-transferase pulldown assay in vitro. Both proteins were colocalized in the extracellular matrix in an osteoblastic cell culture system, and the binding complex was identified in the mineral-associated fraction of bone matrix. Furthermore, LOX suppressed TGF-β1-induced Smad3 phosphorylation likely through its amine oxidase activity. The data indicate that LOX binds to mature TGF-β1 and enzymatically regulates its signaling in bone and thus may play an important role in bone maintenance and remodeling.

Received for publication April 24, 2008. Revision received September 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 DE10489 (to M. Y.) and R21 AR052824 (to M. Y.). 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: CB 7455, Dental Research Center, University of North Carolina, Chapel Hill, NC 27599-7455. Tel.: 919-966-3441; Fax: 919-966-1231; E-mail: Mitsuo_Yamauchi{at}dentistry.unc.edu.

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