Amylin(1-8) is devoid of anabolic activity in bone.
Amylin(1-8), a cyclic peptide consisting of the eight N-terminal amino acids of the 37-amino acid peptide amylin, has been shown to induce proliferation of primary osteoblasts and to induce bone formation in healthy male mice, whereas no data on efficacy in bone disease-related models have been reported. Therefore, we evaluated any effects of amylin(1-8) in ovariectomized rats with established osteopenia, a model for postmenopausal osteoporosis. At doses up to 100 nmol/kg/day, a dose highly effective in healthy mice, amylin(1-8) was unable to increase bone mineral density in ovariectomized rats during an 8-week treatment period. Histomorphometric analysis of the tibia indicated that amylin(1-8) did not change bone histomorphometric parameters. In an attempt to verify any potential biological effects of amylin(1-8), we investigated the efficacy of this peptide in various in vitro assays. Experiments designed to confirm previously published results on the proliferative effects of amylin(1-8) on primary osteoblasts failed to show any response. Amylin(1-8) was able to partially displace (125)I-rat amylin(1-37) from amylin receptors composed of the calcitonin receptor and RAMP1, indicating specific interaction of the peptide with the amylin binding site. However, in vitro efficacy assays with amylin(1-8) in calcitonin receptor-RAMP-positive HEK293T and MCF7 cells failed to reveal any agonist activity of amylin(1-8), whereas amylin(1-37) showed the expected agonist activity. In conclusion, our results indicate that amylin(1-8) does not show agonist activity on amylin receptors, does not affect osteoblast proliferation, and is devoid of anabolic activity in bone.
Ellegaard
Maria
M
Zealand Pharma A/S, 2600 Glostrup, Denmark.
Thorkildsen
Christian
C
Petersen
Solveig
S
Petersen
Jørgen Søberg
JS
Jørgensen
Niklas Rye
NR
Just
Rasmus
R
Schwarz
Peter
P
Ramirez
Maria Teresa
MT
Stahlhut
Martin
M
D000682:Amyloid / Q000494:pharmacology* / Q000627:therapeutic use; D045930:Anabolic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001861:Bone Regeneration / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D010052:Ovariectomy; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000187:drug effects / Q000378:metabolism
D000682:Amyloid; D045930:Anabolic Agents; D047908:Intracellular Signaling Peptides and Proteins; D058228:Islet Amyloid Polypeptide; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; C545502:RAMP1 protein, human; C545505:Ramp1 protein, mouse; C545508:Ramp1 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; C550067:amylin(1-8)