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Evidence for auto/paracrine actions of vitamin D in bone: 1-hydroxylase expression and activity in human bone cells

M. van Driel^*, M. Koedam^*, C. J. Buurman^*, M. Hewison, H. Chiba, A. G. Uitterlinden^*, H. A. P. Pols^* and J. P. T. M. van Leeuwen^*,1

^* Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands;

Division of Medical Sciences, University of Birmingham, Birmingham, UK; and

Department of Pathology, Sapporo Medical University School of Medicine, University of Sapporo, Sapporo, Japan

¹Correspondence: Department of Internal Medicine, Rm. Ee526, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands. E-mail: j.vanleeuwen{at}erasmusmc.nl

ABSTRACT

Vitamin D is an important regulator of mineral homeostasis and bone metabolism. 1-Hydroxylation of 25-(OH)D₃ to form the bioactive vitamin D hormone, 1,25-(OH)₂D_3, is classically considered to take place in the kidney. However, 1-hydroxylase has been reported at extrarenal sites. Whether bone is a 1,25-(OH)₂D₃ synthesizing tissue is not univocal. The aim of this study was to investigate an autocrine/paracrine function for 1,25-(OH)₂D₃ in bone. We show that 1-hydroxlase is expressed in human osteoblasts, as well as the vitamin D binding protein receptors megalin and cubilin. Functional analyses demonstrate that after incubation with the 1-hydoxylase substrate 25-(OH)D_3, the osteoblasts can produce sufficient 1,25-(OH)₂D₃ to modulate osteoblast activity, resulting in induced alkaline phosphatase (ALP) activity, osteocalcin (OC) and CYP24 mRNA expression, and mineralization. The classical renal regulators of 1-hydroxylase, parathyroid hormone, and ambient calcium do not regulate 1-hydroxylase in osteoblasts. In contrast, interleukin (IL)-1ß strongly induces 1-hydroxylase. Besides the bone-forming cells, we demonstrate 1-hydroxylase activity in the bone resorbing cells, the osteoclasts. This is strongly dependent on osteoclast inducer RANKL. This study showing expression, activity, and functionality of 1-hydoxylase unequivocally demonstrates that vitamin D can act in an auto/paracrine manner in bone.—van Driel, M., Koedam, M., Buurman, C. J., Hewison, M., Chiba, H., Uitterlinden, A. G., Pols, H. A. P., van Leeuwen, J. P. T. M. Evidence for auto/paracrine actions of vitamin D in bone: 1-hydroxylase expression and activity in human bone cells.

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