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J. Biol. Chem., Vol. 280, Issue 15, 14476-14484, April 15, 2005

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TSG-6 Protein Binding to Glycosaminoglycans

FORMATION OF STABLE COMPLEXES WITH HYALURONAN AND BINDING TO CHONDROITIN SULFATES^*

Hans-Georg Wisniewski, Evan S. Snitkin, Catalin Mindrescu, Moshe H. Sweet, and Jan Vilcek

From the Department of Microbiology, New York University School of Medicine, New York, New York 10016

TSG-6 protein, up-regulated in inflammatory lesions and in the ovary during ovulation, shows anti-inflammatory activity and plays an essential role in female fertility. Studies in murine models of acute inflammation and experimental arthritis demonstrated that TSG-6 has a strong anti-inflammatory and chondroprotective effect. TSG-6 protein is composed of the N-terminal link module that binds hyaluronan and a C-terminal CUB domain, present in a variety of proteins. Interactions between the isolated link module and hyaluronan have been studied extensively, but little is known about the binding of full-length TSG-6 protein to hyaluronan and other glycosaminoglycans. We show that TSG-6 protein and hyaluronan, in a temperature-dependent fashion, form a stable complex that is resistant to dissociating agents. The formation of such stable complexes may underlie the activities of TSG-6 protein in inflammation and fertility, e.g. the TSG-6-dependent cross-linking of hyaluronan in the cumulus cell-oocyte complex during ovulation. Because adhesion to hyaluronan is involved in cell trafficking in inflammatory processes, we also studied the effect of TSG-6 on cell adhesion. TSG-6 binding to immobilized hyaluronan did not interfere with subsequent adhesion of lymphoid cells. In addition to immobilized hyaluronan, full-length TSG-6 also binds free hyaluronan and all chondroitin sulfate isoforms under physiological conditions. These interactions may contribute to the localization of TSG-6 in cartilage and to its chondroprotective and anti-inflammatory effects in models of arthritis.

Received for publication, October 15, 2004 , and in revised form, January 7, 2005.

^* This work was supported by National Institutes of Health Grant AR-44351 (to H.-G. W.) and a research grant from the Friderika Fischer Foundation (to H.-G. W. and J. V.). 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.

To whom correspondence should be addressed: Dept. of Microbiology, New York University Medical Center, 550 First Ave., New York, NY 10016. Tel.: 212-263-0924; Fax: 212-263-7933; E-mail: hans-georg.wisniewski{at}med.nyu.edu.

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