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J. Biol. Chem., Vol. 281, Issue 51, 39096-39104, December 22, 2006

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Inhibition of Bone Morphogenetic Protein 1 by Native and Altered Forms of ₂-Macroglobulin^*

Yue Zhang¹, Gaoxiang Ge¹, and Daniel S. Greenspan^¶2

From the Program in Cellular and Molecular Biology, the Departments of Pathology and Laboratory Medicine and ^¶Pharmacology, University of Wisconsin, Madison, Wisconsin 53706

The four mammalian bone morphogenetic protein 1 (BMP1)-like proteinases act to proteolytically convert procollagens to the major fibrous components of the extracellular matrix. They also activate lysyl oxidase, an enzyme necessary to the covalent cross-linking that gives collagen fibrils much of their tensile strength. Thus, these four proteinases are attractive targets for interventions designed to limit the excess formation of fibrous collagenous matrix that characterizes fibrosis. Although it has previously been reported that the serum protein ₂-macroglobulin is unable to inhibit the astacin-like proteinases meprin and meprin , we herein demonstrate ₂-macroglobulin to be a potent inhibitor of the similar BMP1-like proteinases. BMP1 is shown to cleave the ₂-macroglobulin "bait" region, at a single specific site, which resembles the sites at which BMP1-like proteinases cleave the C-propeptides of procollagens I–III. ₂-Macroglobulin is an irreversible inhibitor that is shown to bind bone morphogenetic protein 1 in a covalent complex. It is also demonstrated that genetically modified ₂-macroglobulin, in which the native bait region is replaced by sequences flanking the probiglycan BMP1 cleavage site, is enhanced 24-fold in its ability to inhibit BMP1, and is capable of inhibiting the biosynthetic processing of procollagen I by cells. These findings suggest possible therapeutic interventions involving ectopic expression of modified versions of ₂-macroglobulin in the treatment of fibrotic conditions.

Received for publication, February 13, 2006 , and in revised form, October 25, 2006.

^* This work was supported by National Institutes of Health Grants AR47746 and GM71679 (to D. S. G.). 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 To whom correspondence should be addressed: 1300 University Ave., Madison, WI 53706. Tel.: 608-262-4676; Fax: 608-262-6691; E-mail: dsgreens{at}wisc.edu.

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