Vitamin D metabolism, cartilage and bone fracture repair

The 1,25-(OH)2D metabolite mediates the endocrine actions of vitamin D by regulating in the small intestine the expression of target genes that play a critical role in intestinal calcium absorption. The major role of the vitamin D hormone on bone is indirect and mediated through its endocrine function on mineral homeostasis. However, genetic manipulation of the expression of Cyp27b1 or the VDR in chondrocytes strongly support a direct role for locally synthesized 1,25(OH)2D, acting through the VDR, in vascular invasion and osteoclastogenesis during endochondral bone development. Cells from the growth plate respond to the 24,25-(OH)2D and 1,25-(OH)2D metabolites in a cell maturation-dependent manner and the effects of 1,25-(OH)2D are thought to be mediated through binding to the membrane-associated receptor PDIA3 (protein disulfide isomerase associated 3). The physiological relevance of membrane-mediated 1,25-(OH)2D signaling is emerging and is discussed. Finally, preliminary results suggest that mice deficient for Cyp24a1 exhibit a delay in bone fracture healing and support a role for 24,25-(OH)2D in mammalian fracture repair.

► The major role of 1,25-(OH)2D on bone is indirect and mediated through its endocrine function on mineral homeostasis.
► However, mouse molecular genetics has helped determine a transient, specific, direct role for 1,25-(OH)2D genomic signaling in chondrocytes.
► The physiological relevance of membrane-mediated 1,25-(OH)2D signaling through PDIA3 (protein disulfide isomerase associated 3) is emerging.