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 aminoterminal 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 bonecell cultures. The bone-cell action of N-proCT was potentiated with insulin with a >200% increase in DNA synthesis at high insulin concentrations. In sharp contrast to these fridings 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.Calcitonin (CT) is a 32-amino-acid peptide hormone that in mammals is secreted mainly by thyroidal C cells (parafollicular cells). Although its precise role is disputed, CT's primary action is to inhibit bone resorption. This inhibitory action on osteoclasts has been considered the main mechanism for the protective and anabolic skeletal effects ascribed to CT (1-5). Several reports suggest that CT may also have a stimulatory effect on osteoblasts and their progenitors (6)(7)(8). While such diversity of CT effects could explain many of the anabolic skeletal effects associated with C-cell secretory activity, yet another explanation is suggested by recent findings in corticotropin (ACTH) biosynthesis. Non-ACTH peptides cogenerated during processing of the ACTH precursor show ACTH-related bioactivity that is distinct from but complementary to the role of ACTH in stress physiology (9,10). In a similar manner, C cells could exert anabolic skeletal effects via the non-CT secretory peptides cogenerated with CT during processing of procalcitonin (proCT).ProCT has been identified in fish, chickens, rats, and humans (11-13). In each species, proCT is -...

Procalcitonin N-Terminal Peptide Causes Catabolic Effects via the Hypothalamus and Prostaglandin-Dependent Pathways

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Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene

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Calcitonin and Prednisolone Display Antagonistic Actions on Bone and Have Synergistic Effects in Experimental Arthritis

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