SECOND MESSENGERS IN PARATHYROID HORMONE ACTION

Massachusetts General Hospital, Boston MA

Investigators

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Abstract

Description:(Taken directly from the application) The actions of parathyroid hormone (PTH) on bone are diverse and may cause a net gain or loss of skeletal mass, depending upon the temporal and concentration profiles of the circulating hormone. Intermittent (once daily) PTH shows promise for therapy of osteoporosis, but more knowledge of the cellular actions of PTH in bone is needed to enhance the efficacy of this approach. PTH activates PTH/PTHrP receptors (PTHRs) expressed by osteoblasts (OBs) and marrow stromal cells (MSCs) but not by mature osteoclasts (OCLs), although it may exert direct effects on early progenitors of both OBs and OCLs. PTHRs activate multiple parallel effectors-adenylyl cyclase (AC), phospholipase-C (PLC) and cytosolic free calcium transients-that modulate proliferation, differentiation and other functions in target cells of bone, but the links between specific PTHR signals, or patterns of signals, and distinctive programs of cellular responses in each population of target cells are poorly understood. Previous efforts to approach these issues in vitro were constrained by unavailability of homogeneous, nontransformed populations of normal PTH target cells and of specific techniques for modulating their PTHR signaling. The main goal of this project is to utilize novel, conditionally transformed, clonal OB, MSC and OCL progenitor cell lines, in which PTHR expression and signaling can be specifically modified, to determine the roles of the PTHR and of individual PTHR signals in the key cellular effects of the hormone. By eliminating endogenous PTHRs through gene ablation and replacing them with normal or signal-selective mutant PTHRs, a panel of otherwise-identical clonal bone cell lines of each type will be created with which to assess the cellular responses to specific PTHR signals. Together with new signal-selective PTH analogs that can instruct normal PTHRs to signal aberrantly, these cell systems will enable direct in vitro assays of the role of the PTHR and its messenger signals in controlling OB and OCL differentiation, including the possible differential impact of pulsatile and continuous PTH exposures that have opposite effects on bone in vivo. Access to PTHR-null cells also will allow unobscured detection of the effects of other species of PTH receptors that may be expressed normally by these cells. The new understanding of PTH action that should flow from these studies will be invaluable for further development of skeletally active PTH analogs.