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Definition
Osteostatin (OSN) is a fragment of parathyroid hormone-related protein (PTHrP) 107-111, which is responsible for a range of activities related to the modulation of bone formation as well as keratinocyte proliferation 1.

Related Peptides
OSN is a fragment potent inhibitor of osteoclastic bone resorption in rat 2. The hypercalcaemic activity of PTHrP is based on its partial homology to parathyroid hormone (PTH), a protein that regulates calcium homeostasis 3.

Discovery
PTHrP was originally discovered as a systemic humoral factor that is released by tumor cells and causes hypercalcaemia of malignancy (HHM) by Suva et al., in 1987 3.

Structural Characteristics
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-defined4. Osteostatin (1-5) amide (human, bovine, dog, horse, mouse, rabbit, rat) 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 5.

Mode of Action
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 calcitonin6. Osteostatin also bears a number of phosphorylation sites that are important for the mitogenic activity of PTHrP in vascular smooth muscle cells 7.

Functions
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 vascularization and bone formation, and neoangiogenesis in PTHrP-producing tumors 8.  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 1.


References

1.     Cuthbertson RM, Kemp BE, Barden JA (1999). Structure study of osteostatin PTHrP[Thr107](107-139). Biochim Biophys Acta., 1432(1):64-72.

2.     Wang DX, Han R, Liu HY, Huang L, Fu J (1999). An Efficient Synthesis and Screening of Osteostatin analogues by Using Pooling Strategy. Chinese Chemical Letters, 10(10):821-824.
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3.     Dittmer J (2004). The importance of PTHrP for cancer development. Gene Ther Mol Biol., 8:451-464.

4.     Lozano D, Manzano M, Doadrio JC, Salinas AJ, Vallet-Regí M, Gómez-Barrena E, Esbrit P (2009). Osteostatin-loaded bioceramics stimulate osteoblastic growth and differentiation. Acta Biomaterialia.

5.     Whitfield JF, Isaacs RJ, Chakravarthy BR, Durkin JP, Morley P, Neugebauer W, Williams RE, Willick G, Rixon GH (1994). C-terminal fragments of parathyroid hormone-related protein, PTHrP-(107-111) and (107-139), and the N-terminal PTHrP-(1-40) fragment stimulate membrane-associated protein kinase C activity in rat spleen lymphocytes. J. Cell. Physiol. 158:518–522.

6.     Zheng MH, McCaughan HB, Papadimitriou JM, Nicholson GC, Wood DJ (2004). Tartrate resistant acid phosphatase activity in rat cultured osteoclasts is inhibited by a carboxyl terminal peptide (osteostatin) from parathyroid hormone-related protein. J Cellular Biochem., 54 (2): 145 – 153.

7.     Fiaschi-Taesch N, Takane KK, Masters S, Lopez-Talavera JC, and Stewart AF (2004).
Parathyroid Hormone-Related Protein as a Regulator of pRb and the Cell Cycle in Arterial Smooth Muscle. Circulation, 110(2): 177- 185.

8.     Esbrit P, Alvarez-Arroyo MV, De Miguel F, Martin O, Martinez ME and Caramelo C (2000). C-Terminal Parathyroid Hormone-Related Protein Increases Vascular Endothelial Growth Factor in Human Osteoblastic Cells. J Am Soc Nephrol., 11:1085-1092.

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