Previous work showed that retinoic acid stimulates mineralization and induces the formation of matrix vesicles, but its molecular targets remained unknown. In the new study, the authors found that, in cultured growth plate chondrocytes, retinoic acid acts by increasing the transcription of three annexin family proteins and causing them to form calcium channels in the plasma membrane.
Retinoic acid is known to regulate transcription after binding to the retinoic acid receptor complex, but the new results imply that it can also control calcium homeostasis, perhaps through receptors yet to be discovered. After retinoic acid induces an initial calcium influx, the formation of induced annexins into channels in the plasma membrane further boosts cytosolic calcium, increasing annexin expression again and causing the release of matrix vesicles. These vesicles contain annexin channels that allow the entry of crystal-forming calcium.
Excess mineralization has been implicated in several disease processes, including osteoarthritis and the calcification of cardiovascular tissues. Recently, the authors have determined that annexin expression is induced in osteoarthritic chondrocytes. If annexins are as central to pathogenic mineralization as they appear to be in healthy tissue, they could be promising targets for a variety of therapies. ▪