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J. Biol. Chem., Vol. 282, Issue 36, 26418-26430, September 7, 2007

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Potential Role for Heparan Sulfate Proteoglycans in Regulation of Transforming Growth Factor- (TGF-) by Modulating Assembly of Latent TGF--binding Protein-1^*

Qian Chen, Pitchumani Sivakumar, Craig Barley, Donna M. Peters^¶, Ronald R. Gomes^||**, Mary C. Farach-Carson^||, and Sarah L. Dallas¹

From the Department of Oral Biology, School of Dentistry, University of Missouri at Kansas City, Kansas City, Missouri 64108, the Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, the ^¶Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706, the ^||Department of Biological Sciences, University of Delaware, Newark, Delaware 197165, and the ^**Department of Orthopedics & Rehabilitation, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033-0850

Latent transforming growth factor--binding proteins (LTBPs) are extracellular matrix (ECM) glycoproteins that play a major role in storage of latent TGF- in the ECM and regulate its availability. We have previously identified fibronectin as a key molecule for incorporation of LTBP1 and TGF- into the ECM of osteoblasts and fibroblasts. Here we provide evidence that heparan sulfate proteoglycans may mediate binding between LTBP1 and fibronectin. We have localized critical domains in the N terminus of LTBP1 that are required for co-localization with fibronectin in osteoblast cultures and have identified heparin binding sites in the N terminus of LTBP1 between residues 345 and 487. Solid-phase binding assays suggest that LTBP1 does not bind directly to fibronectin but that the binding is indirect. Heparin coupled to bovine serum albumin (heparin-BSA) was able to mediate binding between fibronectin and LTBP1. Treatment of primary osteoblast cultures with heparin or heparin-BSA but not with chondroitin sulfate impaired LTBP1 deposition onto fibronectin without inhibiting expression of LTBP1. Inhibition of LTBP1 incorporation was accompanied by reduced incorporation of latent TGF- into the ECM, with increased amounts of soluble latent TGF-. Inhibition of attachment of glycosaminoglycans to the core proteins of proteoglycans by -D-xylosides also reduced incorporation of LTBP1 into the ECM. These studies suggest that heparan sulfate proteoglycans may play a critical role in regulating TGF- availability by controlling the deposition of LTBP1 into the ECM in association with fibronectin.

Received for publication, April 20, 2007 , and in revised form, June 19, 2007.

^* This work was supported by National Institutes of Health Grants AR051517 and CA75387 (to S. L. D.) and CA098912 (to M. C. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.

¹ To whom correspondence should be addressed: School of Dentistry, University of Missouri, 650 E. 25th St., Kansas City, MO 64108. Tel.: 816-235-6295; Fax: 816-235-5524; E-mail: dallass{at}umkc.edu.

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