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J. Biol. Chem., Vol. 283, Issue 2, 1104-1112, January 11, 2008

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Terminal Differentiation of Chick Embryo Chondrocytes Requires Shedding of a Cell Surface Protein That Binds 1,25-Dihydroxyvitamin D3^*

Rita Dreier, Birgit Kathrin Günther, Tom Mainz, Ilka Nemere, and Peter Bruckner¹

From the Institute for Physiological Chemistry and Pathobiochemistry, University Hospital of Münster, 48149 Münster, Germany and Nutrition and Food Sciences, Utah State University, Logan, Utah 84322

Endochondral ossification comprises a cascade of cell differentiation culminating in chondrocyte hypertrophy and is negatively controlled by soluble environmental mediators at several checkpoints. Proteinases modulate this control by processing protein signals and/or their receptors. Here, we show that insulin-like growth factor I can trigger hypertrophic development by stimulating production and/or activation of proteinases in some populations of chick embryo chondrocytes. Cell surface targets of the enzymes include 1,25-dihydroxyvitamin D3 membrane-associated rapid response steroid receptor (1,25 D3 MARRS receptor), also known as ERp57/GRp58/ERp60. This protein is anchored to the outer surface of plasma membranes and inhibits late chondrocyte differentiation after binding of 1,25-dihydroxyvitamin D3. Upon treatment with insulin-like growth factor I, 1,25 D3 MARRS receptor is cleaved into two fragments of 30 and 22 kDa. This process is abrogated along with hypertrophic development by E-64 or cystatin C, inhibitors of cysteine proteinases. Cell differentiation is enhanced by treatment with antibodies to 1,25 D3 MARRS receptor that either block binding of the inhibitory ligand 1,25-dihydroxyvitamin D3 or inactivate 1,25 D3 MARRS receptor left intact after treatment with proteinase inhibitors. Therefore, proteolytic shedding of 1,25 D3 MARRS receptor constitutes a molecular mechanism eliminating the 1,25-dihydroxyvitamin D3-induced barrier against late cartilage differentiation and is a potentially important step during endochondral ossification or cartilage degeneration in osteoarthritis.

Received for publication, April 20, 2007 , and in revised form, October 25, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 492 B18 (to R. D.) and Grant SFB 492, A2 (to P. B.). 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 two supplemental figures.

¹ To whom correspondence should be addressed: Münster University Hospital, Physiological Chemistry and Pathobiochemistry, Waldeyerstr. 15, 48149 Münster, Germany. Tel.: 49-251-8355591; Fax: 49-251-8355596; E-mail: peter.bruckner{at}uni-muenster.de.

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