Classical Properties of Vitamin D

Traditionally, vitamin D is well known for its role in maintaining blood calcium (Ca2+) and phosphate (PO4) levels underlying bone metabolism. The regulation of bone metabolism is highly complex and requires several hormonal inputs, including parathyroid hormone (PTH), calcitonin, and vitamin D. Although each hormonal contribution is significant to overall bone health and maintenance and in turn, each worthy of their own chapter—vitamin D remains the preeminent subject of focus.

Vitamin D regulates bone metabolism by stimulating calcium reabsorption in both the intestines and kidneys. After 1-α hydroxylase conversion of 25D, 1,25D enters the circulating bloodstream and travels to VDR receptors highly expressed within renal and intestinal epithelial cells. Dimerization of the VDR with the related RXR, allows high-affinity binding with VDREs of genes encoding for TRPV6 and TRPV5, and subsequently increases their expression. TRPV5 and TRPV6 represent a pair of homologous epithelial Ca2+ channels that allow for the active reabsorption of calcium into the blood stream (den Dekker et al. 2003; Nijenhuis et al. 2003). Notably, both TRPV channels have multiple VDREs in their gene promoters and are highly selective for Ca2+ ions as compared to other members of the TRP family. This selectivity for the calcium ion underlies their mechanistic activity in active Ca2+ reabsorption (Van Cromphaut et al. 2001; Weber et al. 2001).

In order to enter the blood stream, Ca2+ needs to travel against its concentration gradient. Current theory proposes that active Ca2+ transport is a highly complex process requiring the extensive cooperation of cellular machinery. Beginning in the lumen, a transmembrane electrochemical gradient drives the influx of Ca2+ ions through TRPV6 channels along the apical membrane of enterocytes and into the cell. While calcium is an important signaling molecule in normal metabolism, an excess of intracellular Ca2+ leads to cell-signaling interference and alterations in metabolic function. 1,25D directly regulates Ca2+ transport by modulating the expression of TRPV6, PMCA, and calbindin-D9k—a calcium-binding protein with two functional Ca2+ binding sites (Hoenderop et al. 2005). PMCA is a Ca2+ ATPase pump believed to be activated by its calmodulin-binding domain, upon binding with calbindin-D9k. Activation of PMCA allows for the facilitation of Ca2+ across the basolateral membrane of enterocytes, and delivery into the circulating blood supply. Furthermore, enterocytes express an auxiliary sodium (Na+)/Ca2+ exchanger (NCX) that aids basolateral transport of Ca2+ into the bloodstream, which is independent of VDR regulation (Hoenderop et al. 2004). Current opinion also suggests that circulating calbindin proteins may directly secret Ca2+ into the bloodstream (Hoenderop et al. 2004; Lambers et al. 2006).

Similarly, vitamin D regulates Ca2+ reabsorption in the distal kidney tubule [26]. Although the names of the particular proteins involved have changed, mechanisms between intestinal and renal Ca2+ reabsorption share the same basic underlying physiology. Within kidney epithelial cells, 1,25D induces TRPV5, PMCA1b (a Ca2+ ATPase pump), and calbindin-D28k (another Ca2+ binding protein) expression, driving calcium reabsorption from the lumen back into the circulating blood supply. Furthermore, the kidney expresses its own version of a VDR-independent sodium (Na+)/Ca2+ exchanger (NCX1), which aids basolateral Ca2+ transport back in the bloodstream (Fig. 3) (Unwin et al. 2004).