A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys

被引：108

作者：

Lotinun, Sutada ^{[1
]}

Pearsall, R. Scott ^{[2
]}

Davies, Monique V. ^{[2
]}

Marvell, Tod H. ^{[2
]}

Monnell, Travis E. ^{[2
]}

Ucran, Jeffrey ^{[2
]}

Fajardo, Roberto J. ^{[3
,4
]}

Kumar, Ravindra ^{[2
]}

Underwood, Kathryn W. ^{[2
]}

Seehra, Jasbir ^{[2
]}

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

Baron, Roland ^{[1
,5
,6
]}

机构：

[1] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA

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

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

[4] Beth Israel Deaconess Med Ctr, Orthoped Biomech Lab, Boston, MA 02215 USA

[5] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA

[6] Harvard Univ, Sch Med, Boston, MA 02114 USA

来源：

BONE | 2010年 / 46卷 / 04期

关键词：

Activin A; ActRIIA; Osteoporosis; Osteoblast; Osteoclast; PARATHYROID-HORMONE; 1-34; FACTOR-BETA FAMILY; POSTMENOPAUSAL WOMEN; MACACA-FASCICULARIS; FOLLISTATIN SYSTEM; BINDING PROTEIN; OSTEOPOROSIS; CULTURES; DIFFERENTIATION; EXPRESSION;

D O I：

10.1016/j.bone.2010.01.370

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Activin A belongs to the TGF-beta superfamily and plays an important role in bone metabolism. It was reported that a soluble form of extracellular domain of the activin receptor type IIA (ActRIIA) fused to the Fc domain of murine IgG, an activin antagonist, has an anabolic effect on bone in intact and ovariectomized mice. The present study was designed to examine the skeletal effect of human ActRIIA-IgG1-Fc (ACE-011) in non-human primates. Young adult female Cynomolgus monkeys were given a biweekly subcutaneous injection of either 10 mg/kg ACE-011 or vehicle (VEH) for 3 months. Treatment effects were evaluated by histomorphometric analysis of the distal femur, femoral midshaft, femoral neck and 12th thoracic vertebrae, by mu CT analysis of femoral neck and by biomarkers of bone turnover. Compared to VEH, at the distal femur ACE-011-treated monkeys had significantly increased cancellous bone volume (+93%), bone formation rate per bone surface (+166%) and osteoblast surface (+196%) indicating an anabolic action. Monkeys treated with ACE-011 also had decreased osteoclast surface and number. No differences were observed in parameters of cortical bone at the midshaft of the femur. Similar to distal femur, ACE-011-treated monkeys had significantly greater cancellous bone volume, bone formation rate and osteoblast surface at the femoral neck relative to VEH. A significant increase in bone formation rate and osteoblast surface with a decrease in osteoclast surface was observed in thoracic vertebrae. mu CT analysis of femoral neck indicated more plate-like structure in ACE-011-treated monkeys. Monkeys treated with ACE-011 had no effect on serum bone-specific alkaline phosphatase and CTX at the end of the study. These observations demonstrate that ACE-011 is a dual anabolic-antiresorptive compound, improving cancellous bone volume by promoting bone formation and inhibiting bone resorption in non-human primates. Thus, soluble ActRIIA fusion protein may be useful in the prevention and/or treatment of osteoporosis and other diseases involving accelerated bone loss. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：1082 / 1088

页数：7