CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24.
The CYP24A1 enzyme (25-hydroxyvitamin D-24-hydroxylase) not only is involved in the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)2D] but also generates the 24,25-dihydroxyvitamin D [24,25(OH)2D] metabolite. The biological activity of 24,25(OH)2D remains controversial. While in vitro studies suggest that primary cultures of rat rib chondrocytes respond to 24,25(OH)2D in a maturation-specific manner and that the metabolite is necessary for the cells to progress from a proliferating, immature status to a differentiated, 1,25(OH)2D-responsive stage, in vivo evidence to support this putative role remains lacking. Studies in chicken showed increases in serum levels of 24,25(OH)2D and of the renal mRNA levels of Cyp24a1 following fracture, suggesting a role for 24,25(OH)2D in fracture repair. The Cyp24a1-deficient mouse strain represents an invaluable tool to examine the putative role of 24,25(OH)2D in mammalian fracture repair. We have compared fracture repair between Cyp24a1-/- mice and wild-type controls. We have observed a delay in the mineralization of the cartilaginous matrix of the soft callus in Cyp24a1-/- mutant animals, accompanied by reduced expression of chondrocyte marker genes. These results show that Cyp24a1 deficiency delays fracture repair and strongly suggest that vitamin D metabolites hydroxylated at position 24, such as 24,25(OH)2D3, play an important role in the mechanisms leading to normal fracture healing.
Genetics Unit, Shriners Hospital for Children, and Department of Human Genetics, Medicine and Surgery, McGill University, Montreal, Quebec, Canada H3A 2T5. rst-arnaud@shriners.mcgill.ca
René
R
St-Arnaud
D000818:Animals; D001842:Bone and Bones; D002645:Chickens; D019902:Chondrocytes / Q000166:cytology; D004703:Endocrine System; D017102:Fracture Healing; D006132:Growth Plate / Q000378:metabolism; D006900:Hydroxylation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018167:Receptors, Calcitriol / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D018167:Receptors, Calcitriol; D014807:Vitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase