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

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.