HAPLOINSUFFICIENCY OF PARATHYROID HORMONE-RELATED PEPTIDE (PTHRP) RESULTS IN ABNORMAL POSTNATAL BONE-DEVELOPMENT

Although apparently phenotypically normal at birth, mice heterozygous for inactivation of the gene encoding parathyroid hormone-related pept ide (PTHrP) develop haplotype insufficiency by 3 months of age. In add ition to histologic and morphologic abnormalities similar to those see n in homozygous mutants, heterozygous animals demonstrated alterations in trabecular bone and bone marrow These included metaphyseal bone sp icules which were diminished in volume, irregularly distributed, and l ess well developed than those seen in age-matched controls as well as bone marrow, which contained an inordinate number of adipocytes. A sub stantial reduction in PTHrP mRNA was detected in heterozygous tissue, while circulating parathyroid hormone (PTH) and calcium concentrations were normal. Thus, while a physiologic concentration of PTH was capab le of maintaining calcium homeostasis, it was incapable of compensatin g for PTHrP haploinsufficiency in developing bone. In normal animals, both PTHrP and the PTH/PTHrP receptor were expressed predominantly in chondrocytes situated throughout the proliferative zone of the tibial growth plate. In the metaphysis, the PTH/PTHrP receptor was identified on osteoblasts and preosteoblastic cells situated in the bone marrow, while PTHrP was expressed only by osteoblasts. These observations ind icate that postnatal bone development involves susceptible pathways th at display exquisite sensitivity to critical levels of PTHrP and imply that the skeletal effects of PTH are influenced by locally produced P THrP. Moreover, identification of both the ligand and its N-terminal r eceptor in metaphyseal osteoblasts and their progenitors suggests an a utocrine/paracrine role for the protein in osteoblast differentiation and/or function. Impairment in this function as a consequence of PTHrP haploinsufficiency may critically influence the course of bone format ion, resulting in altered trabecular architecture and perhaps low bone mass and increased bone fragility. (C) 1996 Academic Press, Inc.