In vitro and in vivo activities of C-terminally truncated PTH peptides reveal a disconnect between cAMP signaling and functional activity

There is considerable evidence implicating the cAMP-signaling pathway in the anabolic action of PTH; and to date, all PTH and PTHrp peptides that stimulate cyclic AMP are active in animal models of osteogenesis. We have tested two C-terminally truncated peptides, PTH(1–29) and a modified PTH(1–21) (...

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Bibliographic Details
Published in:Bone (New York, N.Y.) N.Y.), 2004-12, Vol.35 (6), p.1263-1272
Main Authors: Murrills, Richard J., Matteo, Jeanne J., Samuel, Rachelle L., Andrews, Jennifer L., Bhat, Bheem M., Coleburn, Valerie E., Kharode, Yogendra P., Bex, Frederick J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Bone Density - drug effects
Bone Density - physiology
Bone mineral density
Calcium Signaling - drug effects
Calcium Signaling - physiology
Cell Line, Tumor
CRE
Cyclic AMP - physiology
Dose-Response Relationship, Drug
Female
G-protein signaling
Humans
Investigative techniques, diagnostic techniques (general aspects)
Medical sciences
Osteoarticular system. Muscles
Osteoblasts
Parathyroid Hormone - metabolism
Parathyroid Hormone - pharmacology
Parathyroid Hormone - physiology
Peptide Fragments - metabolism
Peptide Fragments - pharmacology
Peptide Fragments - physiology
Protein Binding - drug effects
Protein Binding - physiology
PTH/PTHrP
Radiodiagnosis. Nmr imagery. Nmr spectrometry
Rats
Rats, Sprague-Dawley
Receptors, Parathyroid Hormone - metabolism
Receptors, Parathyroid Hormone - physiology
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Summary:There is considerable evidence implicating the cAMP-signaling pathway in the anabolic action of PTH; and to date, all PTH and PTHrp peptides that stimulate cyclic AMP are active in animal models of osteogenesis. We have tested two C-terminally truncated peptides, PTH(1–29) and a modified PTH(1–21) (MPTH(1–21)), in in vitro and in vivo assays of PTH action. Each of the C-terminally truncated peptides was of low nanomolar potency in assays of receptor binding and cAMP stimulation. However, when we tested these peptides for functional response in Saos-2 cells stably transfected with a cyclic AMP response element (CRE) reporter, the C-terminally truncated peptides were two to four times less potent than would be expected from their binding and cAMP-stimulating properties. Furthermore, PTH(1–29), although active, was approximately 20-fold less potent than PTH(1–34) in a rat model of osteogenesis while MPTH(1–21) was inactive. The relative lack of activity of these peptides in vivo suggests that while activation of the cAMP pathway may be important for the anabolic effect of PTH fragments, it is not, of itself, predictive of their in vivo activity.
ISSN:8756-3282
1873-2763
DOI:10.1016/j.bone.2004.08.015