Osteostatins

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Introduction

Osteostatin (OSN) is a fragment potent inhibitor of osteoclastic bone resorption in rat. The hypercalcaemic activity of PTHrP is based on its partial homology to parathyroid hormone (PTH), a protein that regulates calcium homeostasis.

PTHrP is an important regulator of bone remodeling. Recent studies show that this protein can induce osteogenic features through its N- and C-terminal domains. Silica-based ordered mesoporous bioceramics with an SBA-15 structure known to be bioactive and biocompatible have recently been evaluated for their capacity to uptake and deliver L-tryptophan. This amino acid corresponds to the end position of the 107-111 domain (called osteostatin) of the native C-terminal PTHrP (107-139) fragment, whose true action in bone metabolism is still ill-defined. Osteostatin (1-5) amide H-Thr-Arg-Ser-Ala-Trp-NH₂. This pTH-related protein fragment stimulated membrane-associated protein kinase C in freshly isolated rat spleen lymphocytes and thus raises the possibility of being a physiological regulator of the proliferation and other activities of lymphocytes.

Mechanism of action

Osteostatin (OSN) has an inhibitory effect on bone resorption in vitro and in vivo. It exerts its inhibitory effect in a biphasic manner on TRAcP activity, inhibiting its secretion and either suppressing its synthesis or increasing its degradation. In addition, osteostatin induced rapid cellular retraction of both human and rat cultured osteoclasts, which was morphologically distinct from that produced by calcitonin. Osteostatin also bears a number of phosphorylation sites that are important for the mitogenic activity of PTHrP in vascular smooth muscle cells.

Application of Osteostatin

Osteostatin (OSN) has been shown to inhibit bone resorption in rodents both in vitro and in vivo. In addition, local injection of low doses of one of these peptides to mouse calvaria decreases the number of osteoblasts, while intermittent administration of high doses of osteostatin into ovariectomized rats decreases trabecular bone formation, but restores cortical bone mass. Another function of OSN is that it increases the VEGF that has potential implications for both bone vas-cularization and bone formation, and neoangiogenesis in PTHrP-producing tumors. Anti-mitogenic properties of OSN have been detected in breast cancer cells and cytosolic calcium is used by OSN to signal in some neurons through a non-PTH receptor, unlike the separate circulating N-terminal domain.

References

1. Cuthbertson, R. M., Kemp, B. E., & Barden, J. A. (1999). Structure study of osteostatin PTHrP [Thr107] (107–139). Biochimica Biophysica Acta, 1432(1), 64–72.
2. Fiaschi-Taesch, N. (2004). Parathyroid Hormone-Related Protein as a Regulator of pRb and the Cell Cycle in Arterial Smooth Muscle. Circulation, 110(2), 177–185.