Hedgehog and Vitamin D Signaling Pathways in Development and Disease

The classic physiological activity associated with the vitamin D scaffold is the maintenance of calcium and phosphorous homeostasis in the bone. This activity is commonly attributed to direct binding of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3, calcitriol], the hormonally active form of vitamin D, to the vitamin D receptor (VDR). More recently, calcitriol and VDR have been shown to control the expression of genes associated with cellular proliferation and differentiation in a wide variety of cells, suggesting more extensive biological activities for the vitamin D system. Recently, calcitriol and several structurally related members of the vitamin D class of seco-steroids have demonstrated the ability to regulate the hedgehog (Hh) signaling pathway. Hh signaling plays an essential role with respect to tissue differentiation during embryogenesis and maintains stem cell populations in certain adult tissues. Potential mechanisms of cross talk between the two signaling pathways highlight our evolving understanding of the complexities of calcitriol/VDR signaling and suggest a cooperative role during multiple stages of human development and disease.