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

Sato T, Verma S, Khatri A, Dean T, Goransson O, Gardella TJ, Wein MN

JBMR plus6 May 2021Cited by 24 (Europe PMC)

PMID33977197PMCIDPMC8101618DOI10.1002/jbm4.10441PepBankPUB-33977197

Summary

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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study16

16 results from studies that gave the peptide. No result from this study comes from people.

01LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from hPTH (1-34) in receptor internalization.
In plain wordsIn cells, abaloparatide did not differ significantly from hPTH (1-34) in receptor internalization.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeReceptor internalization
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719701
02LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from LA-PTH in receptor internalization.
In plain wordsIn cells, abaloparatide did not differ significantly from LA-PTH in receptor internalization.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeReceptor internalization
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719702
03LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from hPTH (1-34) in β-arrestin recruitment.
In plain wordsIn cells, abaloparatide did not differ significantly from hPTH (1-34) in β-arrestin recruitment.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeβ-arrestin recruitment
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719703
04LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from LA-PTH in β-arrestin recruitment.
In plain wordsIn cells, abaloparatide did not differ significantly from LA-PTH in β-arrestin recruitment.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeβ-arrestin recruitment
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719704
05LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from hPTH (1-34) in intracellular calcium stimulation.
In plain wordsIn cells, abaloparatide did not differ significantly from hPTH (1-34) in intracellular calcium stimulation.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeIntracellular calcium stimulation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719705
06LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from LA-PTH in intracellular calcium stimulation.
In plain wordsIn cells, abaloparatide did not differ significantly from LA-PTH in intracellular calcium stimulation.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeIntracellular calcium stimulation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719706
07LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from hPTH (1-34) in cAMP generation.
In plain wordsIn cells, abaloparatide did not differ significantly from hPTH (1-34) in cAMP generation.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changecAMP generation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719707
08LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide did not differ significantly from LA-PTH in cAMP generation.
In plain wordsIn cells, abaloparatide did not differ significantly from LA-PTH in cAMP generation.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changecAMP generation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719708
09LabIn vitro (cells)Mechanism
In cell washout studies, abaloparatide produced significantly faster PTH1R recycling than hPTH (1-34).
In plain wordsIn cells, abaloparatide produced faster receptor recycling than hPTH (1-34).
Peptide
Abaloparatide (Tymlos)
Outcome
IncreasePTH1R recycling speed
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
However, abaloparatide showed significantly quicker PTH1R recycling in washout studies.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719709
10LabIn vitro (cells)Mechanism
In cell washout studies, abaloparatide produced significantly faster PTH1R recycling than LA-PTH.
In plain wordsIn cells, abaloparatide produced faster receptor recycling than LA-PTH.
Peptide
Abaloparatide (Tymlos)
Outcome
IncreasePTH1R recycling speed
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
However, abaloparatide showed significantly quicker PTH1R recycling in washout studies.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719710
11LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide had comparable effects on SIK2 phosphorylation to hPTH (1-34).
In plain wordsIn cells, abaloparatide had similar effects on SIK2 phosphorylation to hPTH (1-34).
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeSIK2 phosphorylation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719711
12LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide had comparable effects on SIK2 phosphorylation to LA-PTH.
In plain wordsIn cells, abaloparatide had similar effects on SIK2 phosphorylation to LA-PTH.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeSIK2 phosphorylation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719712
13LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide had comparable effects on SIK substrate dephosphorylation to hPTH (1-34).
In plain wordsIn cells, abaloparatide had similar effects on SIK substrate dephosphorylation to hPTH (1-34).
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeSIK substrate dephosphorylation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719713
14LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide had comparable effects on SIK substrate dephosphorylation to LA-PTH.
In plain wordsIn cells, abaloparatide had similar effects on SIK substrate dephosphorylation to LA-PTH.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeSIK substrate dephosphorylation
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719714
15LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide had comparable effects on downstream gene expression to hPTH (1-34).
In plain wordsIn cells, abaloparatide had similar effects on downstream gene expression to hPTH (1-34).
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeDownstream gene expression changes
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
hPTH (1-34)
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719715
16LabIn vitro (cells)Mechanism
In cell-based assays, abaloparatide had comparable effects on downstream gene expression to LA-PTH.
In plain wordsIn cells, abaloparatide had similar effects on downstream gene expression to LA-PTH.
Peptide
Abaloparatide (Tymlos)
Outcome
No significant changeDownstream gene expression changes
Study
n: not reported in source
Cell-based PTH1R signaling assays
Comparator
LA-PTH
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Here, we directly compared short-term effects of hPTH (1-34), abaloparatide, and LA-PTH in multiple cell-based PTH1R signaling assays.
Show in the study text Report a problemFND-3397719716

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
22 Oct 2026, 02:25 UTC
Study results updated
Version 1
21 Oct 2026, 18:59 UTC
First added · source update from Europe PMC

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Keywords

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