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) (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.
Murrills
Richard J
RJ
Department of Osteoporosis, Women's Health Research Institute, Wyeth Research, Collegeville, PA 19426, USA. murrilr@wyeth.com
Matteo
Jeanne J
JJ
Samuel
Rachelle L
RL
Andrews
Jennifer L
JL
Bhat
Bheem M
BM
Coleburn
Valerie E
VE
Kharode
Yogendra P
YP
Bex
Frederick J
FJ
D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism / Q000502:physiology
D010281:Parathyroid Hormone; D010446:Peptide Fragments; D018016:Receptors, Parathyroid Hormone; C023443:carboxyl-terminal parathyroid hormone; D000242:Cyclic AMP