Review
Studies on the mechanisms of the skeletal anabolic action of endogenous and exogenous parathyroid hormone

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Abstract

Parathyroid hormone (PTH) has been viewed as catabolic for bone. Nevertheless, exogenous PTH is anabolic when administered intermittently, at a frequency that permits complete clearance between doses. In the fetus and neonate, endogenous PTH is required for normal trabecular bone formation. In older animals PTH produces net bone loss in fulfilling its calcium homeostatic role, whereas PTH-related peptide (PTHrP), acting in a paracrine/autocrine mode, is anabolic. The proliferative, differentiating, and anti-apoptotic effects of PTH on cells of the osteoblast lineage leading to anabolism can be direct, or indirect via release of local growth factors. The anabolic effect of PTH is also influenced by osteoclastic activity such that suppression of osteoclasts with anti-resorptive agents, concomitant to administering PTH, may enhance the anabolic effect by delaying a reactive osteoclastic response. In contrast, prolonged suppression of osteoclast activity prior to administering PTH appears to diminish molecular signals that increase the osteoblast pool and thereby reduces the anabolic efficacy of PTH. These observations may define the proper timing of the use of PTH as a therapeutic in diseases of bone loss. Finally, the capacity of exogenous PTH to modulate extra-osseous factors such as 1,25 dihydroxyvitamin D may also modulate its potency as an anabolic agent.

Section snippets

Evidence for a physiologic skeletal anabolic role for endogenous PTH and PTHrP

To address this first issue we assessed, using a genetic approach, whether there is a skeletal anabolic role for endogenous PTH and PTHrP which can be unmasked by eliminating PTH and/or PTHrP [26]. We thus examined the phenotypes of mice with targeted deletion of the genes encoding PTH (PTH−/−), PTHrP (PTHrP−/−) and both PTH and PTHrP (PTH−/−PTHrP−/−). We found that although both ligands appear to act via the common PTHR1, there were striking differences in the phenotypes of the null mutants.

Molecular modulation of the osteoblast pool by PTH and PTHrP

PTH and PTHrP appear to exert a large part of their anabolic effect by modulating the size and activity of the osteoblast pool either directly or indirectly. In view of the increase in marrow fat observed in association with reduced trabecular bone in mice with PTHrP haploinsufficiency, we assessed the possibility that one of the functions of PTHrP might be to regulate the commitment of mesenchymal stem cells toward the osteoblastic rather than the adipocytic lineage [36]. For this purpose we

Effect of alterations in osteoclast activity on the capacity of PTH to exert an anabolic effect

During the bone remodeling cycle, osteoclast activation and formation of a resorption cavity is followed by osteoblast influx and the production of new bone (Fig. 3). One of the molecular mechanisms linking osteoclasts and osteoblasts in this process is believed to be the release of growth factors such as transforming growth factor beta (TGFβ), BMPs and IGFs from resorbed bone which can stimulate osteoblasts and increase the active osteoblast pool. It has also been suggested that although full

Effect of endogenous vitamin D on the anabolic action of PTH

The vast majority of studies on the mechanisms of the anabolic effects of PTH have focused on examination of the local direct or indirect actions of the peptide which are stimulatory or inhibitory in bone. However, PTH as a systemically active hormone, may cause perturbations in extra-osseous sites which could potentially impinge on the skeleton and therefore on its skeletal action. Consequently, we assessed whether the interaction of PTH with the vitamin D endocrine system could have

Summary

Endogenous PTH, classically believed to function as a bone resorbing hormone to maintain calcium homeostasis, clearly has a critical role to play in the development and maintenance of trabecular bone mass, particularly in the fetus and the neonate. Endogenous PTHrP, acting as a paracrine/autocrine substance can also play a role in maintaining bone mass in the older animal although its major role in the fetus is to modulate the development of the cartilaginous growth plate. The capacity of

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research.

The author acknowledge the essential contributions of Geoffrey N. Hendy, Andy Karaplis, Richard Kremer, Dengshun Miao, Dibyendu Panda, and Rana Samadfam without whom this work would not have been possible. The author acknowledge the excellent service provided by the McGill Centre for Bone and Periodontal Research and the CIHR Skeletal Health Training Program.

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