TARGETED OVEREXPRESSION OF PARATHYROID HORMONE-RELATED PEPTIDE IN CHONDROCYTES CAUSES CHONDRODYSPLASIA AND DELAYED ENDOCHONDRAL BONE-FORMATION

Parathyroid hormone-related peptide (PTHrP) was initially identified a s a product of malignant tumors that mediates paraneoplastic hypercalc emia. It is now known that the parathyroid hormone (PTH) and PTRrP gen es are evolutionarily related and that the products of these two genes share a common receptor, the PTH/PTHrP receptor, PTHrP and the PTH/PT BrP receptor are widely expressed in both adult and fetal tissues, and recent gene-targeting and disruption experiments have implicated PTHr P as a developmental regulatory molecule. Apparent PTHrP functions inc lude the regulation of endochondral bone development, of hair follicle formation, and of branching morphogenesis in the breast. Herein, we r eport that overexpression of PTHrP in chondrocytes using the mouse typ e II collagen promoter induces a novel form of chondrodysplasia charac terized by short-limbed dwarfism and a delay in endochondral ossificat ion. This features a delay in chondrocyte differentiation and in bone collar formation and is sufficiently marked that the mice are born wit h a cartilaginous endochondral skeleton. In addition to the delay, cho ndrocytes in the transgenic mice initially become hypertrophic at the periphery of the developing long bones rather than in the middle, lead ing to a seeming reversal in the pattern of chondrocyte differentiatio n and ossification. By 7 weeks, the delays in chondrocyte differentiat ion and ossification have largely corrected, leaving foreshortened and misshapen but histologically near-normal bones. These findings confir m a role for PTHrP as an inhibitor of the program of chondrocyte diffe rentiation. PTHrP may function in this regard to maintain the stepwise differentiation of chondrocytes that initiates endochondral ossificat ion in the midsection of endochondral bones early in development and t hat also permits linear growth at the growth plate later in developmen t.