Activated parathyroid hormone/parathyroid hormone-related protein receptorin osteoblastic cells differentially affects cortical and trabecular bone

Parathyroid hormone (PTH), an important regulator of calcium homeostasis, t argets most of its complex actions in bone to cells of the osteoblast linea ge. Furthermore, PTH is known to stimulate osteoclastogenesis indirectly th rough activation of osteoblastic cells. To assess the role of the PTH/PTH-r elated protein receptor (PPR) in mediating the diverse actions of PTH on bo ne in vivo, we generated mice that express, in cells of the osteoblastic li neage, one of the the constitutively active re ccp tors described in Jansen 's metaphyseal chondrodysplasia. In these transgenic mice, osteoblastic fun ction was increased in the trabecular and endosteal compartments, whereas i t was decreased in the periosteum. In trabecular bone of the transgenic mic e, there was an increase in osteoblast precursors, as well as in mature ost eoblasts. Osteoblastic expression of the constitutively active PPR induced a dramatic increase in osteoclast number in both trabecular and compact bon e in transgenic animals. The net effect of these actions was a substantial increase in trabecular bone volume and a decrease in cortical bone thicknes s of the long bones, These findings, for the first time to our knowledge, i dentify the PPR as a crucial mediator of both bone-forming and bone-resorbi ng actions of PTH, and they underline the complexity and heterogeneity of t he osteoblast population and/or their regulatory microenvironment.