A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

被引：40

作者：

Baud'huin, Marc ^{[2
]}

Solban, Nicolas ^{[1
]}

Cornwall-Brady, Milton ^{[1
]}

Sako, Dianne ^{[1
]}

Kawamoto, Yoshimi ^{[1
]}

Liharska, Katia ^{[1
]}

Lath, Darren ^{[2
]}

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

Underwood, Kathryn W. ^{[1
]}

Ucran, Jeffrey ^{[1
]}

Kumar, Ravindra ^{[1
]}

Pobre, Eileen ^{[1
]}

Grinberg, Asya ^{[1
]}

Seehra, Jasbir ^{[1
]}

Canalis, Ernesto ^{[5
]}

Pearsall, R. Scott ^{[1
]}

Croucher, Peter I. ^{[2
,6
]}

机构：

[1] Acceleron Pharma Inc, Cambridge, MA 02139 USA

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

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

[4] Harvard Univ, Sch Med, Boston, MA 02215 USA

[5] St Francis Hosp & Med Ctr, Dept Res, Hartford, CT 06105 USA

[6] Garvan Inst Med Res, Sydney, NSW 2010, Australia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 30期

关键词：

anabolic; therapy; MOUSE EMBRYOGENESIS; DICKKOPF PROTEINS; MULTIPLE-MYELOMA; DEFECT MODEL; OSTEOBLASTS; DKK1; MICE; SUPPRESSION; OSTEOCLASTS; EXPRESSION;

D O I：

10.1073/pnas.1204929109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Diseases such as osteoporosis are associated with reduced bone mass. Therapies to prevent bone loss exist, but there are few that stimulate bone formation and restore bone mass. Bone morphogenetic proteins (BMPs) are members of the TGF beta superfamily, which act as pleiotropic regulators of skeletal organogenesis and bone homeostasis. Ablation of the BMPR1A receptor in osteoblasts increases bone mass, suggesting that inhibition of BMPR1A signaling may have therapeutic benefit. The aim of this study was to determine the skeletal effects of systemic administration of a soluble BMPR1A fusion protein (mBMPR1A-mFc) in vivo. mBMPR1A-mFc was shown to bind BMP2/4 specifically and with high affinity and prevent downstream signaling. mBMPR1A-mFc treatment of immature and mature mice increased bone mineral density, cortical thickness, trabecular bone volume, thickness and number, and decreased trabecular separation. The increase in bone mass was due to an early increase in osteoblast number and bone formation rate, mediated by a suppression of Dickkopf-1 expression. This was followed by a decrease in osteoclast number and eroded surface, which was associated with a decrease in receptor activator of NF-kappa B ligand (RANKL) production, an increase in osteoprotegerin expression, and a decrease in serum tartrate-resistant acid phosphatase (TRAP5b) concentration. mBMPR1A treatment also increased bone mass and strength in mice with bone loss due to estrogen deficiency. In conclusion, mBMPR1A-mFc stimulates osteoblastic bone formation and decreases bone resorption, which leads to an increase in bone mass, and offers a promising unique alternative for the treatment of bone-related disorders.

引用

页码：12207 / 12212

页数：6

共 37 条

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