title: Procalcitonin's amino-terminal cleavage peptide is a bone-cell mitogen.
abstract: The parafollicular-cell (C-cell) hormone calcitonin (CT) can preserve or even augment skeletal mass by inhibiting osteoclast-mediated bone resorption. The possibility of an additional anabolic skeletal influence has also been raised: C cells might, via CT or other secretory products, affect osteoblast-mediated bone formation. The 57-residue amino-terminal procalcitonin cleavage peptide, N-proCT, has recently been identified in human and rat C cells, where it is made and secreted in equimolar amounts with CT. The coelaboration of N-proCT and CT and N-proCT's sequence conservation during evolution prompted us to investigate the potential skeletal bioactivity of N-proCT. We found that synthetic human N-proCT, at nanomolar concentrations, stimulated proliferation of normal and neoplastic human osteoblasts. At maximally effective doses, human N-proCT caused more than a 100% increase above the control rate of DNA synthesis, an effect comparable to the maximal growth effect of insulin, a potent mitogen for osteoblasts. Human N-proCT exerted a similar maximal mitogenic effect in chicken osteoblast cultures but at 1000-fold greater concentrations than in human bone-cell cultures. The bone-cell action of N-proCT was potentiated with insulin with a greater than 200% increase in DNA synthesis at high insulin concentrations. In sharp contrast to these findings for N-proCT, the other bioactive C-cell peptides, CT and somatostatin, showed no mitogenic effects in human or chicken osteoblast cultures. Our results indicate that the action of N-proCT on cultured bone cells is separate from and potentiated by insulin, a known growth factor. Unlike insulin and related growth factors such as insulin-like growth factor I, N-proCT is not mitogenic in skin fibroblast cultures. We propose that N-proCT is a C-cell hormone that promotes bone formation via stimulatory actions on osteoblasts and preosteoblasts.
authors.affiliation: Research Service, American Lake Department of Veterans Affairs Medical Center, Tacoma, WA 98493.
authors.forename: D M
authors.initials: DM
authors.lastname: Burns
authors.forename: J M
authors.initials: JM
authors.lastname: Forstrom
authors.forename: K E
authors.initials: KE
authors.lastname: Friday
authors.forename: G A
authors.initials: GA
authors.lastname: Howard
authors.forename: B A
authors.initials: BA
authors.lastname: Roos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002116:Calcitonin / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004247:DNA / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D008934:Mitogens; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D012689:Sequence Homology, Nucleic Acid
chemical_list: C000606589:CALCA protein, human; C000606591:Calca protein, rat; D006023:Glycoproteins; D008934:Mitogens; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D002116:Calcitonin; D004247:DNA; D015740:Calcitonin Gene-Related Peptide