The effects of some peptide hormones on osteoblast-like cells : With specific focus on oxytocin and vasopressin

University dissertation from Stockholm : Karolinska Institutet, Department of Molecular Medicine

Abstract: The nonapeptides oxytocin (OXT) and vasopressin (AVP) are mainly produced in the hypothalamus and released into the circulation through the neurohypophysis. Recently, an OXT-receptor was demonstrated in human osteoblast-like (hOB) cells, and it has been suggested that patients with central diabetes insipidus (deficiency of AVP) have decreased bone mass. Insulin-like growth factor-I (IGF-I), parathyroid hormone (PM), and PTH-related protein (PTHrP) are hormones that have known anabolic effects on bone metabolism. These hormones, as well as AVP, increase the production of nitric oxide (NO) from endothelial cells. NO is also produced in osteoblasts (OB) and participates in the regulation of bone metabolism. One of the aims of the present studies was to investigate the effects of OXT and AVP on OBlike cells. Primary cultures of human OB-like (hOB) cells were prepared from trabecular bone material obtained during knee- and hip-joint replacement surgery. An osteosarcoma cell line (SaOS-2) was used as well. A second aim was to evaluate whether NO was involved in the effects of AVP, IGF-I and PTH/PTHrP For this purpose, bone marrow cells with an OB-phenotype derived from endothelial nitric oxide synthase knockout (eNOSKO) mice and their wild type (WT) counterparts were studied. OXT and AVP increased the proliferation and protein synthesis of OB-like cells. The effects were found in concentrations close to physiological (10- 100 pmol/l) and were abolished by an OXT- and V 1 - receptor antagonist or a proteinkinase C inhibitor, respectively. These findings indicate that the effects of OXT and AVP were mediated through receptors specific to these peptides. In addition, the expression of mRNA for the V 1 a-receptor in hOB cells was demonstrated by RT-PCR. OXT and AVP decreased the production of interleukin-6 from h0B cells and AVP decreased the production of macrophage colony-stimulating factor (MCSF) as well. Neither AVP nor IGF-I induced an increase in cell proliferation in OB-like cells derived from eNOSKO mice, whereas an increase in cell proliferation could be demonstrated in cells derived from WT mice, as well as in cells from eNOSKO mice incubated with an NO donor, SNAP. Thus NO might be involved in the effects of AVP and IGF-I on OB-like cells. In contrast, the increase in cell proliferation in response to PTH and PTHrP seemed to be independent of NO synthesis, since PTH and PTHrP increased cell proliferation in cells from both WT and eNOSKO mice. In conclusion, OXT and AVP increased proliferation of OB-like cells and for the first time mRNA for an AVP-receptor was demonstrated in h0B cells. It is likely that OXT and AVP also may be of importance for bone metabolism in vivo. These peptides or their analogues may, in the future, be used therapeutically for the prevention of osteopenia or the treatment of osteoporosis.

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