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Published online 3 June 2002. doi:10.1083/jcb.200203014
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© The Rockefeller University Press, 0021-9525/2002/6/1061 $5.00
The Journal of Cell Biology, Volume 157, Number 6, June 10, 2002 1061-1070

Article

 Retinoic acid stimulates annexin-mediated growth plate chondrocyte mineralization

Wei Wang1 and Thorsten Kirsch1,2

1 Musculoskeletal Research Laboratory, Department of Orthopaedics and Rehabilitation
2 Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033

Address correspondence to Thorsten Kirsch, Dept. of Orthopaedics and Rehabilitation, H089, Penn State College of Medicine, Hershey Medical Center, 500 University Dr., Hershey, PA 17033. Tel.: (717) 531-7788. Fax: (717) 531-1607. E-mail: tkirsch{at}psu.edu

Biomineralization is a highly regulated process that plays a major role during the development of skeletal tissues. Despite its obvious importance, little is known about its regulation. Previously, it has been demonstrated that retinoic acid (RA) stimulates terminal differentiation and mineralization of growth plate chondrocytes (Iwamoto, M., I.M. Shapiro, K. Yagumi, A.L. Boskey, P.S. Leboy, S.L. Adams, and M. Pacifici. 1993. Exp. Cell Res. 207:413–420). In this study, we provide evidence that RA treatment of growth plate chondrocytes caused a series of events eventually leading to mineralization of these cultures: increase in cytosolic calcium concentration, followed by up-regulation of annexin II, V, and VI gene expression, and release of annexin II–, V–, VI– and alkaline phosphatase–containing matrix vesicles. Cotreatment of growth plate chondrocytes with RA and BAPTA-AM, a cell permeable Ca2+ chelator, inhibited the up-regulation of annexin gene expression and mineralization of these cultures. Interestingly, only matrix vesicles isolated from RA-treated cells that contained annexins, were able to take up Ca2+ and mineralize, whereas vesicles isolated from untreated or RA/BAPTA-treated cells, that contained no or only little annexins were not able to take up Ca2+ and mineralize. Cotreatment of chondrocytes with RA and EDTA revealed that increases in the cytosolic calcium concentration were due to influx of extracellular calcium. Interestingly, the novel 1,4-benzothiazepine derivative K-201, a specific annexin Ca2+ channel blocker, or antibodies specific for annexin II, V, or VI inhibited the increases in cytosolic calcium concentration in RA-treated chondrocytes. These findings indicate that annexins II, V, and VI form Ca2+ channels in the plasma membrane of terminally differentiated growth plate chondrocytes and mediate Ca2+ influx into these cells. The resulting increased cytosolic calcium concentration leads to a further up-regulation of annexin II, V, and VI gene expression, the release of annexin II–, V–, VI– and alkaline phosphatase–containing matrix vesicles, and the initiation of mineralization by these vesicles.

Key Words: annexin; calcium; matrix vesicles; mineralization; retinoic acid


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