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Calcium Research Laboratory and Department of Medicine (D.M., G.N.H., D.G.), McGill University Health Centre and Royal Victoria Hospital, McGill University, Montreal, Canada H3A 1A1; Department of Medicine and Lady Davis Institute for Medical Research (B.H., X.-Y.B., X.-K.T., A.C.K.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Canada H3T 1E2; and Department of Oral and Developmental Biology (B.L.), Forsyth Institute and Harvard School of Dental Medicine, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Andrew C. Karaplis, Jewish General Hospital, 3755 Cote Ste Catherine Road, Montreal, Canada H3T 1E2. E-mail: akarapli{at}ldi.jgh.mcgill.ca.
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 D3 [1,25(OH)2D3] 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 
-hydroxylase expression increased despite the absence of PTH, leading to a rise in circulating 1,25(OH)2D3 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)2D3 can be mobilized, even in the absence of PTH, to guard against extreme calcium deficiency.
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