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Comparable Initial Engagement of Intracellular Signaling Pathways by Parathyroid Hormone Receptor Ligands Teriparatide, Abaloparatide, and Long-Acting PTH.

ABSTRACT: Multiple analogs of parathyroid hormone, all of which bind to the PTH/PTHrP receptor PTH1R, are used for patients with osteoporosis and hypoparathyroidism. Although ligands such as abaloparatide, teriparatide (hPTH 1-34 [TPTD]), and long-acting PTH (LA-PTH) show distinct biologic effects with respect to skeletal and mineral metabolism endpoints, the mechanistic basis for these clinically-important differences remains incompletely understood. Previous work has revealed that differential signaling kinetics and receptor conformation engagement between different PTH1R peptide ligands. However, whether such acute membrane proximal differences translate into differences in downstream signaling output remains to be determined. Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays. At the time points and ligand concentrations utilized, no significant differences were observed between these three ligands at the level of receptor internalization, β-arrestin recruitment, intracellular calcium stimulation, and cAMP generation. However, abaloparatide showed significantly quicker PTH1R recycling in washout studies. Downstream of PTH1R-stimulated cAMP generation, protein kinase A regulates gene expression via effects on salt inducible kinases (SIKs) and their substrates. Consistent with no differences between these ligands on cAMP generation, we observed that hPTH (1-34), abaloparatide, and LA-PTH showed comparable effects on SIK2 phosphorylation, SIK substrate dephosphorylation, and downstream gene expression changes. Taken together, these results indicate that these PTH1R peptide agonists engage downstream intracellular signaling pathways to a comparable degree. It is possible that differences observed in vivo in preclinical and clinical models may be related to pharmacokinetic factors. It is also possible that our current in vitro systems are insufficient to perfectly match the complexities of PTH1R signaling in bona fide target cells in bone in vivo. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

SUBMITTER: Sato T

PROVIDER: S-EPMC8101618 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Intermittent administration of PTH type 1 receptor (PTH1R) agonists increases bone remodeling, with greater stimulation of bone formation relative to bone resorption causing net gains in bone mass. This pharmacodynamic feature underlies the bone-building effects of teriparatide and abaloparatide, the only PTH1R agonists approved to reduce osteoporotic fracture risk in postmenopausal women. This study in 8-week-old female mice compared bone resorption and formation responses to these agents delivered at the same 10 μg/kg dose, and a 40 μg/kg abaloparatide dose was also included to reflect its 4-fold higher approved clinical dose. Peptides or vehicle were administered by daily supra-calvarial subcutaneous injection for 12 days, and local (calvarial) and systemic (L5 vertebral and tibial) responses were evaluated by histomorphometry. Terminal bone histomorphometry data indicated that calvarial resorption cavities were similar in both abaloparatide groups versus vehicle controls, whereas the teriparatide group had more calvarial resorption cavities compared with the vehicle or abaloparatide 40 μg/kg groups. The bone resorption marker serum CTX was significantly lower in the abaloparatide 40 μg/kg group and similar in the other two active treatment groups compared with vehicle controls. Both peptides increased trabecular bone formation rate (BFR) in L5 and proximal tibia versus vehicle, and L5 BFR was higher with abaloparatide 40 μg/kg versus teriparatide. At the tibial diaphysis, periosteal BFR was higher with abaloparatide 40 μg/kg versus vehicle or teriparatide, and endocortical BFR was higher with teriparatide but not with abaloparatide 10 or 40 μg/kg versus vehicle. Few differences in structural or microarchitectural bone parameters were observed with this brief duration of treatment. In summary, calvarial bone resorption cavity counts were higher in the teriparatide group versus the vehicle and abaloparatide 40 μg/kg groups, and the abaloparatide 40 μg/kg group had lower serum CTX versus vehicle. L5 and tibial trabecular bone formation indices were higher in all three active treatment groups versus vehicle. The abaloparatide 40 μg/kg group had higher L5 trabecular BFR and tibial periosteal BFR versus teriparatide, whereas tibial endocortical BFR was higher with teriparatide but not abaloparatide. Together, these findings in female mice indicate that an improved balance of bone formation versus bone resorption is established shortly after initiating treatment with abaloparatide.

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Comparable Initial Engagement of Intracellular Signaling Pathways by Parathyroid Hormone Receptor Ligands Teriparatide, Abaloparatide, and Long-Acting PTH.

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