Differential Regulation of Growth Plate Chondrocytes by 1α,25-(OH)₂D₃and 24R,25-(OH)₂D₃ Involves Cell-maturation-specific Membrane-receptor-activated Phospholipid Metabolism

Abstract

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. PKCalpha 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 PKCzeta, 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.

Regulation of Prostaglandin Metabolism by Calcitriol Attenuates Growth Stimulation in Prostate Cancer Cells

“…This indeed was the case as shown by the decrease in PGE 2 levels in the conditioned media from LNCaP cells following calcitriol treatment. Calcitriol regulation of PGE 2 synthesis and secretion has been also reported in growth plate chondrocytes (44), in monocytes (43,45), and in interleukin-1h-stimulated rheumatoid synovial fibroblasts (46). The effects of calcitriol on PG synthesis and signaling in these target cells seem to be related to the rapid nongenomic actions of calcitriol (47).…”

Endocrine Regulation of the Growth Plate

“…24,25-dihydroxyvitamin D 3 injected directly into rachitic chick growth plates resulted in healing [76]. In vitro, 24,25-dihydroxyvitamin D 3 stimulates differentiation but decreases proliferation in resting zone cells, while 1,25-dihydroxyvitamin D 3 decreases proliferation in resting and proliferative zones [77]. These effects appear to be mediated by a signal transduction pathway in chondrocytes involving cell surface receptors, phospholipases, prostaglandins, and the mitogen-activated protein kinase cascade [78].…”

CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders

“…Since circulating levels of active vitamin D were decreased in Cyp24 -/-F Tg mice, a plausible explanation stems from the likelihood that it is the tissue levels of 1,25(OH) 2 D that increase due to local production by CYP27B1 in association with a completely ineffective catabolic pathway, in other words, a total absence of CYP24 activity. Cyp24 expression is not unique to the proximal renal tubule epithelium but has been observed in many other tissues including the parathyroid glands, chondrocytes, and enterocytes (23,24). Therefore, rising tissue levels of 1,25(OH) 2 D in renal and intestinal epithelial cells would increase calcium transport, while in the parathyroid cells, it would cause the observed decrease in PTH secretion.…”