Chronic kidney disease and vitamin D metabolism in human bone marrow-derived MSCs

Vitamin D that is synthesized in the skin or is ingested undergoes sequential steps of metabolic activation via a cascade of cytochrome P450 enzymatic hydroxylations in the liver and kidney to produce 1α,25-dihydroxyvitamin D (1α,25(OH)₂ D). There are many tissues that are able to synthesize 1α,25(OH)₂ D, but the biological significance of extrarenal hydroxylases is unresolved. Human marrow-derived mesenchymal stem cells (marrow stromal cells, hMSCs) give rise to osteoblasts, and their differentiation is stimulated by 1α,25(OH)₂ D. In addition to being targets of 1α,25(OH)₂ D, hMSCs can synthesize it; on the basis of those observations, we further examined the local autocrine/paracrine role of vitamin D metabolism in osteoblast differentiation. Research with hMSCs from well-characterized subjects provides an innovative opportunity to evaluate the effects of clinical attributes on the regulation of hMSCs. Like the renal 1α-hydroxylase, the enzyme in hMSCs is constitutively decreased with age and chronic kidney disease (CKD); both are regulated by PTH1-34, insulin-like growth factor 1, calcium, 1α,25(OH)₂ D, 25(OH)D, and fibroblast growth factor 23. CKD is associated with impaired renal biosynthesis of 1α,25(OH)₂ D, low bone mass, and increased fracture risk. Studies with hMSCs from CKD patients or aged subjects indicate that circulating 25(OH)D may have an important role in osteoblast differentiation on vitamin D metabolism and action in hMSCs.