Targeted ablation of the 25-hydroxyvitamin D 1 alpha-hydroxylase enzyme: Evidence for skeletal, reproductive, and immune dysfunction

The active form of vitamin D, 1 alpha ,25-dihydroxyvitamin D [1 alpha ,25(O H)(2)D], is synthesized from its precursor 25 hydroxyvitamin D [25(OH)D] vi a the catalytic action of the 25(OH)D-1 alpha -hydroxylase [1 alpha (OH)ase ] enzyme. Many roles in cell growth and differentiation have been attribute d to 1,25(OH)(2)D. including a central role in calcium homeostasis and skel etal metabolism. To investigate the in vivo functions of 1,25(OH)(2)D and t he molecular basis of its actions, we developed a mouse model deficient in l alpha(OH)ase by targeted ablation of the hormone-binding and heme-binding domains of the 1 alpha(OH)ase gene. After weaning, mice developed hypocalc emia, secondary hyperparathyroidism, retarded growth, and the skeletal abno rmalities characteristic of rickets. These abnormalities are similar to tho se described in humans with the genetic disorder vitamin D dependent ricket s type I [VDDR-I; also known as pseudovitamin D-deficiency rickets (PDDR)]. Altered non-collagenous matrix protein expression and reduced numbers of o steoclasts were also observed in bone. Female mutant mice were infertile an d exhibited uterine hypoplasia and absent corpora lutea. Furthermore, histo logically enlarged lymph nodes in the vicinity of the thyroid gland and a r eduction in CD4- and CD8- positive peripheral T lymphocytes were observed. Alopecia, reported in vitamin D receptor (VDR)-deficient mice and in humans with VDDR-II, was not seen, The findings establish a critical role for the 1 alpha (OH)ase enzyme in mineral and skeletal homeostasis as well as in f emale reproduction and also point to an important role in regulating immune function.