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Parathyroid Hormone-Related Peptide Is Required for Increased Trabecular Bone Volume in Parathyroid Hormone-Null Mice

Calcium Research Laboratory of the McGill University Health Center (D.M., J.L., Y.X., D.G.), Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital (H.S., A.C.K.), and Department of Medicine, McGill University, Montréal, Québec, Canada

Address all correspondence and requests for reprints to: Dr. David Goltzman, Calcium Research Laboratory, Royal Victoria Hospital, 687 Pine Avenue W, Room H4.67, Montréal, Québec, Canada H3A 1A1. E-mail: david.goltzman{at}mcgill.ca.

We investigated the relative contributions of PTH and PTHrP to the skeletal phenotype of mice deficient in PTH (PTH^–/–). PTH^–/– mice and PTH^–/– mice lacking one allele encoding PTHrP (PTH^–/–PTHrP^+/–) were compared. Both mutants displayed similar biochemical abnormalities of hypoparathyroidism, but skeletal PTHrP mRNA and protein were decreased in PTH^–/–PTHrP^{+/ –} mice. PTH^–/– mice had increased trabecular bone volume with diminished bone turnover. PTHrP haploinsufficiency reduced trabecular bone of the PTH^–/– mice to levels below those in wild-type animals by decreasing osteoprogenitor cell recruitment, enhancing osteoblast apoptosis, and diminishing bone formation. The results show that the increased trabecular bone volume in PTH-deficient mice is due to diminished PTH-induced osteoclastic bone resorption and persistent PTHrP-stimulated osteoblastic bone formation. They also illustrate the changing role of PTHrP during bone development, demonstrate its bone- forming function in the postnatal state, and support its pharmacological potential as an anabolic agent.

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