brush border and basolateral membranes by processes that do not all require new protein synthesis. The molecular action of 1,25(OH)2D on bone is more complex and controversial as it is both direct and indirect. Much of the skeletal effect is attributed to the provision of adequate calcium and phosphate from the diet by stimulation of their intestinal absorption. However, like PTH, 1,25(OH)2D can induce RANKL in osteoblasts to regulate osteoclast activity and proteins such as osteocalcin and alkaline phosphatase, which may regulate the mineralization process by osteoblasts. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of intestinal calcium and phosphate transport or bone resorption.
Specific receptors for 1,25(OH)2D (VDR) exist in nearly all tissues, not just intestine, bone, and kidney. As a result much effort has been made to develop analogs of 1,25(OH)2D that will target these non-classic target tissues without increasing serum calcium. These non-classic actions include regulation of the secretion of PTH, insulin, and renin; regulation of innate and adaptive immune function through actions on dendritic cell and T-cell differentiation; enhanced muscle function; and proliferation and differentiation of a number of cancer cells. Thus, the potential clinical utility of 1,25(OH)2D and its analogs is expanding.