Skeletal abnormalities in Pth-null mice are influenced by dietary calcium.
We have examined the role of PTH in the postnatal state in a mouse model of PTH deficiency generated by targeting the Pth gene in embryonic stem cells. Mice homozygous for the ablated allele, when maintained on a normal calcium intake, developed hypocalcemia, hyperphosphatemia, and low circulating 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels consistent with primary hypoparathyroidism. Bone turnover was reduced, leading to increased trabecular and cortical bone volume in PTH-deficient mice. When mutant mice were placed on a low-calcium diet, renal 25-hydroxyvitamin D 1 alpha-hydroxylase expression increased despite the absence of PTH, leading to a rise in circulating 1,25(OH)(2)D(3) levels, marked osteoclastogenesis, and profound bone resorption. These studies demonstrate the dependence of the skeletal phenotype in animals with genetically depleted PTH on the external environment as well as on internal hormonal and ionic circulatory factors. They also show that, although PTH action is the first defense against hypocalcemia, 1,25(OH)(2)D(3) can be mobilized, even in the absence of PTH, to guard against extreme calcium deficiency.
Miao
Dengshun
D
Calcium Research Laboratory, Department of Medicine, McGill University Health Centre and Royal Victoria Hospital, McGill University, Montreal, Canada.
He
Bin
B
Lanske
Beate
B
Bai
Xiu-Ying
XY
Tong
Xin-Kang
XK
Hendy
Geoffrey N
GN
Goltzman
David
D
Karaplis
Andrew C
AC
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001847:Bone Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D016723:Bone Remodeling / Q000502:physiology; D001862:Bone Resorption / Q000209:etiology; D001842:Bone and Bones / Q000502:physiology*; D002136:Calcium, Dietary / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004872:Ergocalciferols / Q000097:blood; D006706:Homeostasis / Q000502:physiology*; D006720:Homozygote; D007011:Hypoparathyroidism / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010010:Osteoclasts / Q000473:pathology; D010280:Parathyroid Glands / Q000473:pathology; D010281:Parathyroid Hormone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D002136:Calcium, Dietary; D004872:Ergocalciferols; D010281:Parathyroid Hormone; C003564:1,25-dihydroxyergocalciferol; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase