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J. Biol. Chem., Vol. 283, Issue 16, 10310-10317, April 18, 2008

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Collagen/Annexin V Interactions Regulate Chondrocyte Mineralization^*

From the Musculoskeletal Research Laboratories, Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland 21201

Physiological mineralization in growth plate cartilage is highly regulated and restricted to terminally differentiated chondrocytes. Because mineralization occurs in the extracellular matrix, we asked whether major extracellular matrix components (collagens) of growth plate cartilage are directly involved in regulating the mineralization process. Our findings show that types II and X collagen interacted with cell surface-expressed annexin V. These interactions led to a stimulation of annexin V-mediated Ca²⁺ influx resulting in an increased intracellular Ca²⁺ concentration, [Ca²⁺]_i, and ultimately increased alkaline phosphatase activity and mineralization of growth plate chondrocytes. Consequently, stimulation of these interactions (ascorbate to stimulate collagen synthesis, culturing cells on type II collagen-coated dishes, or overexpression of full-length annexin V) resulted in increase of [Ca²⁺]_i, alkaline phosphatase activity, and mineralization of growth plate chondrocytes, whereas inhibition of these interactions (3,4-dehydro-L-proline to inhibit collagen secretion, K-201, a specific annexin channel blocker, overexpression of N terminus-deleted mutant annexin V that does not bind to type II collagen and shows reduced Ca²⁺ channel activities) decreased [Ca²⁺]_i, alkaline phosphatase activity, and mineralization. In conclusion, the interactions between collagen and annexin V regulate mineralization of growth plate cartilage. Because annexin V is up-regulated during pathological mineralization events of articular cartilage, it is possible that these interactions also regulate pathological mineralization.

Received for publication, October 11, 2007 , and in revised form, January 16, 2008.

^* This work was supported by NIAMS/National Institutes of Health Grants R01AR046245 and R01AR049074 (to T. K.). 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: New York University Hospital for Joint Diseases, Musculoskeletal Research Center, Dept. of Orthopaedic Surgery, 301 E. 17th St., Suite 1500, New York, NY 10003. Tel.: 212-598-6589; Fax: 212-598-6096; E-mail: Thorsten.Kirsch{at}nyumc.org.

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