Inhibiting Activin-A Signaling Stimulates Bone Formation and Prevents Cancer-Induced Bone Destruction In Vivo

被引：107

作者：

Chantry, Andrew D. ^{[1
]}

Heath, Debby ^{[1
]}

Mulivor, Aaron W. ^{[2
]}

Pearsall, Scott ^{[2
]}

Baud'huin, Marc ^{[1
]}

Coulton, Les ^{[1
]}

Evans, Holly ^{[1
]}

Abdul, Nicole ^{[1
]}

Werner, Eric D. ^{[2
]}

Bouxsein, Mary L. ^{[3
,4
]}

Key, Michelle L. ^{[5
]}

Seehra, Jasbir ^{[2
]}

Arnett, Timothy R. ^{[5
]}

Vanderkerken, Karin ^{[6
]}

Croucher, Peter ^{[1
]}

机构：

[1] Univ Sheffield, Sch Med, Dept Human Metab, Mellanby Ctr Bone Res, Sheffield S10 2RX, S Yorkshire, England

[2] Acceleron Pharma, Cambridge, MA USA

[3] Beth Israel Deaconess Med Ctr, Orthopaed Biomech Lab, Boston, MA 02215 USA

[4] Harvard Univ, Sch Med, Boston, MA USA

[5] UCL, Dept Cell & Dev Biol, London, England

[6] Vrije Univ Brussel, Dept Hematol & Immunol, Brussels, Belgium

来源：

JOURNAL OF BONE AND MINERAL RESEARCH | 2010年 / 25卷 / 12期

基金：

英国生物技术与生命科学研究理事会;

关键词：

ACTIVIN-A; BREAST CANCER; MYELOMA METASTASIS; ADVANCED MULTIPLE-MYELOMA; TUMOR BURDEN; SKELETAL COMPLICATIONS; FOLLISTATIN SYSTEM; FOLLICULAR-FLUID; BREAST-CANCER; MURINE MODEL; DOUBLE-BLIND; METASTASIS; MICE;

D O I：

10.1002/jbmr.142

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success Stimulating osteoblastic bone formation to promote repair is a novel alternative approach We show that a soluble activin receptor type IIA fusion protein (ActRIIA muFc) stimulates osteoblastogenesis (p < 01), promotes bone formation (p < 01) and increases bone mass in vivo (p < 001) We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption (p < 05) and suppression of bone formation (p < 01) ActRIIA muFc treatment stimulates osteoblastogenesis (p < 01), prevents myeloma-induced suppression of bone formation (p < 05), blocks the development of osteolytic bone lesions (p < 05), and increases survival (p < 05) We also show, in a murine model of breast cancer bone metastasis, that ActRIIA muFc again prevents bone destruction (p < 001) and inhibits bone metastases (p < 05) These findings show that stimulating osteoblastic bone formation with ActRIIA muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer (C) 2010 American Society for Bone and Mineral Research

引用

页码：2357 / 2370

页数：14

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