The good and the bad of vitamin D inactivation

Abstract

While disorders of impaired vitamin D activation and action have long been appreciated, the consequences of abnormalities in pathways leading to the inactivation of vitamin D metabolites have only recently been identified. Two recent articles have shed new light on this area of vitamin D biology. The report by Martineau et al., published in the JCI, describes a pathway in which binding of the vitamin D metabolite 24R,25(OH)2D3 to its effector molecule FAM57B2 plays an important role in endochondral ossification during bone repair. This work follows, and adds to, another recent JCI publication by Roizen et al., showing that rapid inactivation of vitamin D metabolites causes vitamin D deficiency, leading to vitamin D-dependent rickets.

Figure 1. Vitamin D synthesis and metabolism.

(A) Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre–vitamin D, which isomerizes to vitamin D in the skin. Vitamin D can also be obtained from nutrition. Vitamin D–binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-α position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. Although this latter enzyme is widely expressed, the kidney is thought to be the major source of circulating 1,25-dihydroxyvitamin D. (B) Vitamin D metabolites are 24-hydroxylated by CYP24A1. While these metabolites were previously thought to be inactive, binding of 24R,25(OH)₂D₃ to FAM57B2 in the fracture callus leads to the production of lactosylceramide (LacCer), which is essential for the effects of 24,25(OH)₂D on callus formation and fracture healing. While CYP3A4 plays a minor role in normal vitamin D physiology, a dominant gain-of-function mutation in CYP3A4 leading to accelerated vitamin D inactivation has recently been identified as the molecular basis for two cases of early-onset rickets. Vitamin D metabolites thought to be inactive are shown in red.