Vitamin D And Bone

The relationship between vitamin D and bone is, among others, illustrated by the treatment of osteoporosis with vitamin D, which has been studied and discussed in various studies (1,2). In addition, a reduction of fracture risk by treatment with vitamin D has been reported (3-6). Last year, an overview of all randomized trials studying vitamin D treatment in elderly men or women with involutional or postmenopausal osteoporosis has been published (7). However, the effects on calcium and phosphate homeostasis make it difficult to identify whether vitamin D is directly involved in control of bone metabolism. The bone abnormalities in hypo- and hypervitamin D states mostly result of indirect effects because of changes in concentrations of serum calcium and phosphate. For example, studies

From: The Skeleton: Biochemical, Genetic, and Molecular Interactions in Development and Homeostasis Edited by: E. J. Massaro and J. M. Rogers © Humana Press Inc., Totowa, NJ

with patients with hereditary vitamin D-resistant rickets showed that normal mineralization can be achieved by intravenous supplementation of calcium (8-11). Also in mice lacking the VDR, skeletal homeostasis could be preserved in mice with normal mineral ion homeostasis and not in hypocalce-mic VDR-null mice (12).

Albeit, during the last years a couple of in vivo studies with rats provided evidence for a direct anabolic effect of 1,25-(OH)2D3 on bone. Both chronic treatment with 1,25-(OH)2D3 (13) and short-term treatment (14) increased bone formation. Both treatment schemes increased the number of bone-forming cells (osteoblasts) or osteoblast precursor cells, which may underlie the increased bone formation. However, Amling et al. reported an increased osteoblast number, and osteoid volume in the hypocal-cemic VDR-null mice (12). Whether this is mouse-specific is not clear because direct bone anabolic effects of 1,25-(OH)2D3 in osteopenic ovariectomized rats also have been described (15). A direct effect of vitamin D on bone is also suggested as the VDR is present in osteoblasts and precursors of the bone-resorbing cells (osteoclasts) and has more recently been identified in mature osteoclasts by reverse transcription polymerase chain reaction analysis and immunohistochemistry (16-18). A recent study using mice transgenic for VDR under control of an osteoblast-specific (osteocalcin) promoter also indicated the bone anabolic effects of vitamin D by demonstrating a 20% increased trabecular bone volume and increased bone strength and reduced bone resorption surface in mice with enhanced osteo-blast VDR levels (19).

1,25-(OH)2D3 is involved in keeping the balance between bone formation and resorption by direct and indirect effects on both the osteoblasts and the osteoclasts. In the current review, we will discuss the direct effects of 1,25-(OH)2D3 on osteoblast function and mineralization.

INTRODUCTION: OSTEOBLASTS

Osteoblasts are the bone-forming cells and originate, like fibroblasts, adipocytes, and chondro-cytes, from mesenchymal stem cells. The control of and switches in gene expression during proliferation and differentiation of osteoblasts have been extensively studied and described in detail for rat osteoblasts (20). Comparable differentiation profiles have been described for mouse (21,22), chicken (23), and human osteoblasts (24,25). In general, it can be concluded that osteoblasts proceed through a well-defined differentiation process, controlled by lineage specific factors, resulting in mineralization of the extracellular matrix formed and finally in the matrix-embedded osteocyte (for reviews, see refs. 20 and 26). However, the available data show differences in details of expression of the osteoblast phenotype, which may be attributed to various causes like differences between species or origin of the osteoblast (i.e., site in the skeleton: e.g., long bone or calvaria derived). This may also be related to presence or absence of hormones, cytokines, mechanical loading, etc., thereby representing different metabolic stages or different culture conditions (27). In view of these osteoblast characteristics, it is important to appreciate that not only hormonal responses but also other regulatory processes may be different depending on the differentiation status, origin, and in vitro culture conditions of the osteoblasts. In relation to this, the various osteosarcoma cell lines with osteoblastic characteristics used in research (e.g., UMR106, ROS 17/2.8, MG63, SaOS cells) are most likely to represent particular, different differentiation stages of the osteoblast and may show different qualitative and quantitative responses. These aspects will be more exemplified in relation to 1,25-(OH)2D3 responses in the next section.

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