Differential regulation of growth plate chondrocytes by 1α,25-(OH)2D3 and 24R,25-(OH)2D3 involves cell-maturation-specific membrane-receptor-activated phospholipid metabolism

This review discusses the regulation of growth plate chondrocytes by vitamin D-3. Over the past ten years, our understanding of how two vitamin D metabolites, 1alpha,25-(OH)(2)D-3 and 24R,25-(OH)(2)D-3, exert their effects on endochondral ossification has undergone considerable advances through the use of cell biology and signal transduction methodologies. These studies have shown that each metabolite affects a primary target cell within the endochondral developmental lineage. 1alpha,25(OH)(2)D-3 affects primarily growth zone cells, and 24R,25-(OH)(2)D-3 affects primarily resting zone cells. In addition, 24R,25(OH)(2)D-3 initiates a differentiation cascade that results in down-regulation of responsiveness to 24R,25-(OH)(2)D-3 and up-regulation of responsiveness to 1alpha,25-(OH)(2)D-3.1alpha,25-(OH)(2)D-3 regulates growth zone chondrocytes both through the nuclear vitamin D receptor, and through a membrane-associated receptor that mediates its effects via a protein kinase C (PKC) signal transduction pathway. PKCalpha is increased via a phosphatidylinositol-specific phospholipase C (PLC)-dependent mechanism, as well as through the stimulation of phospholipase A(2) (PLA(2)) activity. Arachidonic acid and its downstream metabolite prostaglandin E-2 (PGE(2)) also modulate cell response to 1alpha,25-(OH)(2)D-3- In contrast, 24R,25-(OH)(2) D-3 exerts its effects on resting zone cells through a separate, membrane-associated receptor that also involves PKC pathways. PKCa is increased via a phospholipase D (PLD)mediated mechanism, as well as through inhibition of the PLA(2) pathway. The target-cell-specific effects of each metabolite are also seen in the regulation of matrix vesicles by vitamin D-3. However, the PKC isoform involved is PKC, and its activity is inhibited, providing a mechanism for differential autocrine regulation of the cell and events in the matrix by these two vitamin D-3 metabolites.