Physiological and pharmacological roles of PTH and PTHrP in bone using their shared receptor, PTH1R
Journal article
Martin, T. John, Sims, Natalie A. and Seeman, Ego. (2021). Physiological and pharmacological roles of PTH and PTHrP in bone using their shared receptor, PTH1R. Endocrine Reviews. 42(4), pp. 383-406. https://doi.org/10.1210/endrev/bnab005
Authors | Martin, T. John, Sims, Natalie A. and Seeman, Ego |
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Abstract | Parathyroid hormone (PTH) and the paracrine factor, PTH-related protein (PTHrP), have preserved in evolution sufficient identities in their amino-terminal domains to share equivalent actions upon a common G protein-coupled receptor, PTH1R, that predominantly uses the cyclic adenosine monophosphate-protein kinase A signaling pathway. Such a relationship between a hormone and local factor poses questions about how their common receptor mediates pharmacological and physiological actions of the two. Mouse genetic studies show that PTHrP is essential for endochondral bone lengthening in the fetus and is essential for bone remodeling. In contrast, the main postnatal function of PTH is hormonal control of calcium homeostasis, with no evidence that PTHrP contributes. Pharmacologically, amino-terminal PTH and PTHrP peptides (teriparatide and abaloparatide) promote bone formation when administered by intermittent (daily) injection. This anabolic effect is remodeling-based with a lesser contribution from modeling. The apparent lesser potency of PTHrP than PTH peptides as skeletal anabolic agents could be explained by lesser bioavailability to PTH1R. By contrast, prolongation of PTH1R stimulation by excessive dosing or infusion, converts the response to a predominantly resorptive one by stimulating osteoclast formation. Physiologically, locally generated PTHrP is better equipped than the circulating hormone to regulate bone remodeling, which occurs asynchronously at widely distributed sites throughout the skeleton where it is needed to replace old or damaged bone. While it remains possible that PTH, circulating within a narrow concentration range, could contribute in some way to remodeling and modeling, its main physiological role is in regulating calcium homeostasis. |
Keywords | bone remodeling; bone modeling; osteoporosis; PTH; PTHrP; PTH1R; teriparatide; abaloparatide; osteoblast; cyclic AMP |
Year | 2021 |
Journal | Endocrine Reviews |
Journal citation | 42 (4), pp. 383-406 |
Publisher | Oxford University Press |
ISSN | 0163-769X |
Digital Object Identifier (DOI) | https://doi.org/10.1210/endrev/bnab005 |
Scopus EID | 2-s2.0-85108904516 |
Research or scholarly | Research |
Page range | 383-406 |
Publisher's version | License All rights reserved File Access Level Controlled |
Output status | Published |
Publication dates | |
Online | 10 Feb 2021 |
Publication process dates | |
Deposited | 22 Nov 2021 |
https://acuresearchbank.acu.edu.au/item/8x1v9/physiological-and-pharmacological-roles-of-pth-and-pthrp-in-bone-using-their-shared-receptor-pth1r
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