Shared pathways of osteoblast mitogenesis induced by amylin, adrenomedullin, and IGF-1.
Amylin and adrenomedullin, members of the calcitonin peptide family, are anabolic to bone. Here, we report overlapping molecular mechanisms by which amylin, adrenomedullin, and IGF-1 induce osteoblast proliferation. Co-treatment of osteoblastic cells with amylin or adrenomedullin and IGF-1 failed to induce an additive mitogenic effect. In osteoblastic cells, neutralization of the IGF-1 receptor blocked the proliferative effects of amylin and adrenomedullin, while neutralization of IGF-1 did not. Neither amylin- nor adrenomedullin-induced mitogenic signaling or cell proliferation in IGF-1 receptor-null fibroblasts. In addition, amylin and adrenomedullin receptor blockers inhibited the proliferative effects of IGF-1 in osteoblastic cells. These findings demonstrate overlap in the molecular mechanisms by which amylin, adrenomedullin, and IGF-1 induce mitogenesis in osteoblasts, and an important role for the IGF-1 receptor in the mitogenic actions of amylin and adrenomedullin. Our findings are potentially important in refining these peptides for the therapy of osteoporosis.
Cornish
Jillian
J
Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. j.cornish@auckland.ac.nz
Grey
Andrew
A
Callon
Karen E
KE
Naot
Dorit
D
Hill
Bernadine L
BL
Lin
Cindy Q X
CQ
Balchin
Leanne M
LM
Reid
Ian R
IR
D053607:Adrenomedullin; D000682:Amyloid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D058228:Islet Amyloid Polypeptide; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D008934:Mitogens; D010455:Peptides; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide; D016212:Transforming Growth Factor beta; D053607:Adrenomedullin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go