PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway

Abstract

After the initial signaling action of parathyroid hormone (PTH) on bone was shown to be activation of adenylyl cyclase, its target was found to be cells of the osteoblast lineage, to the exclusion of osteoclasts and their precursors. This led to the view that the osteoblast lineage regulated osteoclast formation, a proposal that was established when the molecular mechanisms of osteoclast formation were discovered. This is in addition to the effect of PTH1Rv signaling throughout the osteoblast differentiation process to favour the formation of bone-forming osteoblasts. Initial signaling in the PTH target cells through cAMP and protein kinase A (PKA) activation is extremely rapid, and marked by an amplification process in which the later event, PKA activation, precedes cAMP accumulation in time and is achieved at lower concentrations. All of this is consistent with the existence of “spare receptors”, as is the case with several other peptide hormones. PTH-related protein (PTHrP), that was discovered as a cancer product, shares structural similarity with PTH in the amino-terminal domain that allows the hormone, PTH, and the autocrine/paracrine agent, PTHrP, to share actions upon a common G protein coupled receptor, PTH1R, through which they activate adenylyl cyclase with equivalent potencies. Studies of ligand-receptor kinetics have revealed that the PTH/PTH1R ligand-receptor complex, after initial binding and adenylyl cyclase activation at the plasma membrane, is translocated to the endosome, where adenylyl cyclase activation persists for a further short period. This behavior of the PTH1R resembles that of a number of hormones and other agonists that undergo such endosomal translocation. It remains to be determined whether and to what extent the cellular effects through the PTH1R might be influenced when endosomal is added to plasma membrane activation.

In Vitro Effects of PTH (1-84) on Human Skeletal Muscle-Derived Satellite Cells

“…For the first time, the results show evidence that 30-min PTH treatments do not affect intracellular cAMP production in proliferating hSCs at any of the tested concentrations, whereas in myotubes only 10 −6 and 10 −7 mol/L concentrations are able to trigger significant increases in the cAMP levels ( Figure 3 ). The data obtained, with higher concentrations in the myotubes, are in agreement with the previous research in which the same dosages were responsible for the activation of the cAMP pathway in UMR106 osteogenic sarcoma cells [ 28 ]. The fact that PTH apparently affects only cAMP levels in myotubes can be explained by considering that the basal levels of cAMP in hSCs are high and become low after hSC differentiation in myotubes ( Figure 3 b).…”

“…The action of PTH through its receptors is mainly mediated by the activation of cAMP upon a G-protein-mediated cascade of events [ 28 ].…”

Mutation of Methionine to Asparagine but Not Leucine in Parathyroid Hormone Mimics the Loss of Biological Function upon Oxidation

“…Additionally, our work confirms the relative importance of Met-8 over Met-18 in PTH activation of PTHR1 previously noted, offering an explanation for this via molecular modeling outlining the specific different interactions existing between Met-8 and PTHR1 versus Met-18 and PTHR1. PTH and its analogues are of considerable interest as therapies for diseases of bone and mineral ion metabolism, including osteoporosis and hypoparathyroidism. ,, Thus, an increasing understanding of the molecular interactions between PTH and PTHR1 may provide a rationale and incentive for future drug development based on the structural and biochemical properties of Met for the prevention and treatment of diseases that are related to PTH inactivation by oxidation.…”

Effect of transcutaneous electrical acupoint stimulation on bone metabolism in patients with immobilisation after foot and ankle fracture surgery: a randomised controlled trial study protocol

“… 45 Its target is found to be cells of the osteoblast lineage. 46 In addition, the only Food and Drug Administration-approved anabolic bone agent for the treatment of osteoporosis in the USA is PTH 1-34, or teriparatide. 47 …”

“…PTH has been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodelling 45. Its target is found to be cells of the osteoblast lineage 46. In addition, the only Food and Drug Administration-approved anabolic bone agent for the treatment of osteoporosis in the USA is PTH 1-34, or teriparatide 47…”