title: Differential regulation of growth plate chondrocytes by 1alpha,25-(OH)2D3 and 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.
authors.affiliation: Departments of Orthopaedics, Periodontics, Biochemistry, and Orthodontics, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MS-7774, San Antonio, TX 78229-3900, USA. BayanB@uthscsa.edu
authors.forename: B D
authors.initials: BD
authors.lastname: Boyan
authors.forename: V L
authors.initials: VL
authors.lastname: Sylvia
authors.forename: D D
authors.initials: DD
authors.lastname: Dean
authors.forename: F
authors.initials: F
authors.lastname: Del Toro
authors.forename: Z
authors.initials: Z
authors.lastname: Schwartz
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000378:metabolism; D000818:Animals; D019902:Chondrocytes / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004100:Dihydroxycholecalciferols / Q000378:metabolism*; D005786:Gene Expression Regulation; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D010740:Phospholipases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C116441:2-methyl-1,25-dihydroxyvitamin D3; D004100:Dihydroxycholecalciferols; D018167:Receptors, Calcitriol; D014807:Vitamin D; D015650:24,25-Dihydroxyvitamin D 3; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010740:Phospholipases