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1,25-Dihydroxyvitamin D₃ and 24R,25-Dihydroxyvitamin D₃ Modulate Growth Plate Chondrocyte Physiology via Protein Kinase C-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinase

Departments of Orthopedics, Periodontics, and Biochemistry, University of Texas Health Science Center (Z.S., H.E., V.L.S., V.B., R.R.H., D.L., D.D.D., B.D.B.), San Antonio, Texas 78229; Department of Periodontics, Hebrew University Hadassah (Z.S.), Jerusalem, Israel 91-010; Wilford Hall Medical Center (H.E.), Lackland Air Force Base, Texas 78236; and Department of Food and Nutrition Sciences, Utah State University (D.L.), Logan, Utah 84322

Address all correspondence and requests for reprints to: Barbara D. Boyan, Ph.D., Department of Orthopedics, MSC 7774, University of Texas Health Science, Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900. E-mail: . boyanb{at}uthscsa.edu

Membrane-mediated increases in protein kinase C (PKC) activity and PKC-dependent physiological responses of growth plate chondrocytes to vitamin D metabolites depend on the state of endochondral maturation; 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] regulates growth zone (GC) cells, whereas 24R,25-(OH)₂D₃ regulates resting zone (RC) cells. Different mechanisms, including protein kinase A signaling, mediate the effects of 1,25-(OH)₂D₃ and 24R,25-(OH)₂D₃ on PKC, suggesting that different mechanisms may also regulate any MAPK involvement in the physiological responses. This study used confluent cultures of rat costochondral chondrocytes as a model. 1,25-(OH)₂D₃ stimulated MAPK specific activity in GC in a time- and dose-dependent manner, evident within 9 min. 24R,25-(OH)₂D₃ stimulated MAPK in RC; increases were dose dependent, occurred after 9 min, and were greatest at 90 min. In both cells the effect was due to ERK1/2 activation (p42 > p44 in GC; p42 = p44 in RC). MAPK activation was dependent on PKC, but not protein kinase A. The effect of 1,25-(OH)₂D₃ required phospholipase C, and the effect of 24R,25-(OH)₂D₃ required phospholipase D. Inhibition of cyclooxygenase activity reduced the effect of 1,25-(OH)₂D₃ on MAPK in GC and enhanced the effect of 24R,25-(OH)₂D₃ in RC. Based on MAPK inhibition with PD98059, ERK1/2 MAPK mediated the effect of 24R,25-(OH)₂D₃ on [³H]thymidine incorporation and [³⁵S]sulfate incorporation by RC, but only partially mediated the effect of 1,25-(OH)₂D₃ on GC. ERK1/2 was not involved in the regulation of alkaline phosphatase specific activity by either metabolite. This paper supports the hypothesis that 1,25-(OH)₂D₃ regulates the physiology of GC via rapid membrane-mediated signaling pathways, and some, but not all, of the response to 1,25-(OH)₂D₃ is via the ERK family of MAPKs. In contrast, 24R,25-(OH)₂D₃ exerts its effects on RC via PKC-dependent MAPK. Whereas 1,25-(OH)₂D₃ increases MAPK activity via phospholipase C and increased prostaglandin production, 24R,25-(OH)₂D₃ increases MAPK via phospholipase D and decreased prostaglandin production. The cell specificity, metabolite stereospecificity, and the dependence on PKC argue for the participation of membrane receptors for 1,25-(OH)₂D₃ and 24R,25-(OH)₂D₃ in the regulation of ERK1/2 in the growth plate.

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