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

Abstract

Vitamin D is an important regulator of mineral homeostasis and bone metabolism. 1α‐Hy‐droxylation of 25‐(OH)D 3 to form the bioactive vitamin D hormone, 1α,25‐(OH) 2 D 3, is classically considered to take place in the kidney. However, 1α‐hydroxylase has been reported at extrarenal sites. Whether bone is a 1α,25‐(OH) 2 D 3 synthesizing tissue is not univocal. The aim of this study was to investigate an autocrine/ paracrine function for 1α,25‐(OH) 2 D 3 in bone. We show that 1α‐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 1α‐hydoxylase substrate 25‐(OH)D 3, the osteoblasts can produce sufficient 1α,25‐(OH) 2 D 3 to modulate osteoblast activity, resulting in induced alkaline phosphatase (ALP) activity, osteocalcin (OC) and CYP24 mRNA expression, and mineralization. The classical renal regulators of 1α‐hydroxylase, parathyroid hormone, and ambient calcium do not regulate 1α‐hydroxylase in osteoblasts. In contrast, interleukin (IL)‐1β strongly induces 1α‐hydroxylase. Besides the bone‐forming cells, we demonstrate 1α‐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 1α‐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: 1α‐hydroxylase expression and activity in human bone cells. FASEB J. 20, E1811–E1819 (2006)