TARGETED EXPRESSION OF CONSTITUTIVELY ACTIVE RECEPTORS FOR PARATHYROID-HORMONE AND PARATHYROID HORMONE-RELATED PEPTIDE DELAYS ENDOCHONDRAL BONE-FORMATION AND RESCUES MICE THAT LACK PARATHYROID HORMONE-RELATED PEPTIDE

Mice in which the genes encoding the parathyroid hormone (PTH)-related peptide (PTHrP) or the PTH/PTHrP receptor have been ablated by homolo gous recombination show skeletal dysplasia due to accelerated endochon dral bone formation, and die at birth or in utero, respectively. Skele tal abnormalities due to decelerated chondrocyte maturation are observ ed in transgenic mice where PTHrP expression is targeted to the growth plate, and in patients with Jansen metaphyseal chondrodysplasia, a ra re genetic disorder caused by constitutively active PTH/PTHrP receptor s. These and other findings thus indicate that PTHrP and its receptor are essential for chondrocyte differentiation. To further explore the role of the PTH/PTHrP receptor in this process,,ve generated transgeni c mice in which expression of a constitutively active receptor, HKrk-H 223R, was targeted to the growth plate by the rat alpha 1 (LT) collage n promoter. Two major goals were pursued: (i) to investigate how const itutively active PTH/PTHrP receptors affect the program of chondrocyte maturation; and (ii) to determine whether expression of the mutant re ceptor would correct the severe growth plate abnormalities of PTHrP-ab lated mice (PTHrP-/-). The targeted expression of constitutively activ e PTH/PTHrP receptors led to delayed mineralization, decelerated conve rsion of proliferative chondrocytes into hypertrophic cells in skeleta l segments that are formed by the endochondral process, and prolonged presence of hypertrophic chondrocytes with delay of vascular invasion. Furthermore, it corrected at birth the growth plate abnormalities of PTHrP-/-mice and allowed their prolonged survival. ''Rescued'' animals lacked tooth eruption and showed premature epiphyseal closure, indica ting that both processes involve PTHrP. These findings suggest that re scued PTHrP-/-mice mag gain considerable importance for studying the d iverse, possibly tissue-specific role(s) of PTHrP in postnatal develop ment.