Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex

被引：76

作者：

Winkler, DG ^{[1
]}

Yu, CP ^{[1
]}

Geoghegan, JC ^{[1
]}

Ojala, EW ^{[1
]}

Skonier, JE ^{[1
]}

Shpektor, D ^{[1
]}

Sutherland, MK ^{[1
]}

Latham, JA ^{[1
]}

机构：

[1] Celltech R&D Inc, Dept Gene Funct & Target Validat, Bothell, WA 98021 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2004年 / 279卷 / 35期

关键词：

D O I：

10.1074/jbc.M400521200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Noggin and sclerostin are bone morphogenetic protein (BMP) antagonists that modulate mitogenic activity through sequestering BMPs. Little is known of the interactions among this class of proteins. We show that recombinant sclerostin and noggin bound to each other with high affinity (K-D = 2.92 nM). This observation has been extended to naturally expressed noggin and sclerostin from the rat osteosarcoma cell line, ROS 17/2.8, supporting a role for the complex in natural systems. The noggin-sclerostin complex was competitive with BMP binding and mutually attenuated the activity of each BMP antagonist. Collectively, the data demonstrate a novel and exquisite paradigm for the regulation of BMP activity through direct neutralization of the BMP and activation by co-localized BMP antagonist expression. The pleiotrophic nature of noggin and sclerostin represents a novel mechanism for the fine-tuning of BMP activity in bone homeostasis.

引用

页码：36293 / 36298

页数：6

共 19 条

[1] Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST) [J].

Balemans, W ;

Ebeling, M ;

Patel, N ;

Van Hul, E ;

Olson, P ;

Dioszegi, M ;

Lacza, C ;

Wuyts, W ;

Van den Ende, J ;

Willems, P ;

Paes-Alves, AF ;

Hill, S ;

Bueno, M ;

Ramos, FJ ;

Tacconi, P ;

Dikkers, FG ;

Stratakis, C ;

Lindpaintner, K ;

Vickery, B ;

Foernzler, D ;

Van Hul, W .

HUMAN MOLECULAR GENETICS, 2001, 10 (05) :537-543

[2] Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton [J].

Brunet, LJ ;

McMahon, JA ;

McMahon, AP ;

Harland, RM .

SCIENCE, 1998, 280 (5368) :1455-1457

[3] Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein [J].

Brunkow, ME ;

Gardner, JC ;

Van Ness, J ;

Paeper, BW ;

Kovacevich, BR ;

Proll, S ;

Skonier, JE ;

Zhao, L ;

Sabo, PJ ;

Fu, YH ;

Alisch, RS ;

Gillett, L ;

Colbert, T ;

Tacconi, P ;

Galas, D ;

Hamersma, H ;

Beighton, P ;

Mulligan, JT .

AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (03) :577-589

[4] Bone morphogenetic proteins, their antagonists, and the skeleton [J].

Canalis, E ;

Economides, AN ;

Gazzerro, E .

ENDOCRINE REVIEWS, 2003, 24 (02) :218-235

[5] Skeletal overexpression of noggin results in osteopenia and reduced bone formation [J].

Devlin, RD ;

Du, Z ;

Pereira, RC ;

Kimble, RB ;

Economides, AN ;

Jorgetti, V ;

Canalis, E .

ENDOCRINOLOGY, 2003, 144 (05) :1972-1978

[6] Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts [J].

Gazzerro, E ;

Gangji, V ;

Canalis, E .

JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (12) :2106-2114

[7] The natural history of sclerosteosis [J].

Hamersma, H ;

Gardner, J ;

Beighton, P .

CLINICAL GENETICS, 2003, 63 (03) :192-197

[8] Morphogenesis of digits in the avian limb is controlled by FGFs, TGFβs, and noggin through BMP signaling [J].

Merino, R ;

Gañan, Y ;

Macias, D ;

Economides, AN ;

Sampath, KT ;

Hurle, JM .

DEVELOPMENTAL BIOLOGY, 1998, 200 (01) :35-45

[9] Coordinated expression of noggin and bone morphogenetic proteins (BMPs) during early skeletogenesis and induction of noggin expression by BMP-7 [J].

Nifuji, A ;

Noda, M .

JOURNAL OF BONE AND MINERAL RESEARCH, 1999, 14 (12) :2057-2066

[10]

Pizette S, 2001, DEVELOPMENT, V128, P4463

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