Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist

Journal of Experimental Medicine - Tập 199 Số 6 - Trang 805-814 - 2004
Rutger L. van Bezooijen1, Bernard A.J. Roelen2, Annemieke Visser1, L. van der Wee-Pals1, Edwin de Wilt1, Marcel Karperien1, Herman A. Hamersma3, Socrates E. Papapoulos1, Peter ten Dijke2, Clemens W.G.M. Löwik1
11Department of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
22Division of Cellular Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
33Department of Otolaryngology, Weltevreden Park 1715, South Africa

Tóm tắt

Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is expressed exclusively by osteocytes in mouse and human bone and inhibits the differentiation and mineralization of murine preosteoblastic cells (KS483). Although sclerostin shares some of the actions of the BMP antagonist noggin, we show here that it also has actions distinctly different from it. In contrast to noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12 cells. In addition, sclerostin had no effect on BMP-stimulated Smad phosphorylation and direct transcriptional activation of MSX-2 and BMP response element reporter constructs in KS483 cells. Its unique localization and action on osteoblasts suggest that sclerostin may be the previously proposed osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation.

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Tài liệu tham khảo

1958, J. Bone Joint Surg. Br., 40, 208

1984, Clin. Genet., 25, 175, 10.1111/j.1399-0004.1984.tb00481.x

1988, J. Med. Genet., 25, 200, 10.1136/jmg.25.3.200

2003, Clin. Genet., 63, 192, 10.1034/j.1399-0004.2003.00036.x

1941, Am. J. Surg., 53, 444, 10.1016/S0002-9610(41)90660-8

1946, Radiology., 47, 507, 10.1148/47.5.507

1958, Klin Monatsbl Augenheilkd., 132, 509

1975, J. Bone Joint Surg. Am., 57, 273, 10.2106/00004623-197557020-00026

1982, Rev. Brasil Genet., 5, 825

1983, Neurology., 33, 267, 10.1212/WNL.33.3.267

1994, J. Med. Genet., 31, 976, 10.1136/jmg.31.12.976

1998, Clin. Genet., 53, 497, 10.1111/j.1399-0004.1998.tb02603.x

1986, Am. J. Neuroradiol., 7, 505

2001, Hum. Mol. Genet., 10, 537, 10.1093/hmg/10.5.537

2001, Am. J. Hum. Genet., 68, 577, 10.1086/318811

2002, J. Med. Genet., 39, 91, 10.1136/jmg.39.2.91

2002, Am. J. Med. Genet., 110, 144, 10.1002/ajmg.10401

2004, Mol. Endocrinol, 18, 1, 10.1210/me.2003-0227

1998, Mol. Cell., 1, 673, 10.1016/S1097-2765(00)80067-2

1999, Dev. Biol., 209, 98, 10.1006/dbio.1999.9240

2001, Arthritis Res., 3, 1, 10.1186/ar133

2003, Endocr. Rev., 24, 218, 10.1210/er.2002-0023

1997, Nature., 390, 465, 10.1038/37284

1987, Anal. Biochem., 162, 156

1998, J. Bone Miner. Res., 13, 185, 10.1359/jbmr.1998.13.2.185

2000, J. Bone Miner. Res., 15, 1045, 10.1359/jbmr.2000.15.6.1045

1962, J. Histochem. Cytochem., 10, 741, 10.1177/10.6.741

1996, Bone., 19, 429, 10.1016/S8756-3282(96)00255-4

2002, J. Bone Miner. Res., 17, 394, 10.1359/jbmr.2002.17.3.394

2002, Bone., 31, 661, 10.1016/S8756-3282(02)00903-1

2000, Endocrinology., 141, 1667, 10.1210/endo.141.5.7458

1988, Blood., 72, 1242, 10.1182/blood.V72.4.1242.1242

2000, J. Biol. Chem., 275, 2063, 10.1074/jbc.275.3.2063

2002, J. Biol. Chem., 277, 4883, 10.1074/jbc.M111023200

2002, EMBO J., 21, 1743, 10.1093/emboj/21.7.1743

1999, Bone., 25, 397, 10.1016/S8756-3282(99)00189-1

2003, J. Biol. Chem., 278, 24113, 10.1074/jbc.M301716200

1981, Calcif. Tissue Int., 33, 509, 10.1007/BF02409482

1992, J. Cell. Biochem., 49, 310, 10.1002/jcb.240490315

1996, Ital. J. Anat. Embryol., 101, 25

2000, Bone., 26, 71, 10.1016/S8756-3282(99)00242-2

2001, Development., 128, 4439, 10.1242/dev.128.22.4439

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Journal of Experimental Medicine

Tập 199 Số 6

805-814

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