Vitamin D: direct effects of vitamin D metabolites on bone: lessons from genetically modified mice

Abstract

The vitamin D endocrine system has clear beneficial effects on bone as demonstrated by prevention of rickets in children and by reducing the risk of osteomalacia or osteoporosis in adults or elderly subjects. Depending on the design of the study of genetically modified animals, however, 1,25(OH)2D and the vitamin D receptor (VDR) may have no effect, beneficial or even deleterious direct effects on bone. We present here a comprehensive model of the direct effects of vitamin D on bone. In case of sufficient calcium supply, vitamin D and its metabolites can improve the calcium balance and facilitate mineral deposition in bone matrix largely without direct effects on bone cells, although some beneficial effects may occur via mature osteoblasts, as demonstrated in mice with osteoblast-specific overexpression of VDR or 1α-hydroxylase. In case of calcium deficiency, however, 1,25(OH)2D enhances bone resorption, whereas simultaneously inhibiting bone mineralization, so as to defend serum calcium homeostasis at the expense of bone mass. This dual role probably provides a survival benefit for land vertebrates living in a calcium-poor environment.

Figure 1

Interactions between cells of the osteoblast and osteoclast lineages, including osteocytes and possible role of chondrocytes. The regulatory pathways between osteoblasts and osteocytes and osteoclasts include multiple negative (red) and positive (green) feedback loops as indicated; all potentially modifiable by 1,25(OH)₂D₃. These include release of matrix components, such as transforming growth factor-β (TGFβ) and bone morphogenetic proteins (BMPs) that influence osteoblast activity, and humeral factors that influence mineral homeostasis at distant sites, such as fibroblast growth factor (FGF)-23 on renal phosphate handling. Given these loops, any regulatory effect on one cell type can influence the others. Chondrocyte effects on surrounding cells are also potentially involved. The complexity of these inter-relationships may explain the differential effects of 1,25(OH)₂D₃ in driving anabolic and catabolic outcomes. RANKL, receptor activator of nuclear factor-κB ligand.