A soluble activin type IIA receptor induces bone formation and improves skeletal integrity
- R. Scott Pearsall*,†,
- Ernesto Canalis‡,
- Milton Cornwall-Brady*,
- Kathryn W. Underwood*,
- Brendan Haigis*,
- Jeffrey Ucran*,
- Ravindra Kumar*,
- Eileen Pobre*,
- Asya Grinberg*,
- Eric D. Werner*,
- Vaida Glatt§,
- Lisa Stadmeyer‡,
- Deanna Smith‡,
- Jasbir Seehra*, and
- Mary L. Bouxsein§
- *Acceleron Pharma, Inc., 149 Sidney Street, Cambridge, MA 02139;
- ‡Department of Research, St. Francis Hospital and Medical Center, 114 Woodland Street, Hartford, CT 06105; and
- §Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
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Edited by John T. Potts, Jr., Massachusetts General Hospital, Charlestown, MA, and approved March 21, 2008 (received for review November 29, 2007)
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Fig. 1.ActRIIA–mFc treatment increases trabecular bone formation in normal mice. Static and dynamic histomorphometry parameters were measured in the distal femur. Open bars represent VEH-treated mice, and filled bars represent ActRIIA–mFc-treated mice. (A) Tb BV/TV (%). (B) Trabecular number (mm−1). (C) Trabecular thickness (μm). (D) ES/BS (%). (E) Nob/Bpm (mm−1). (F) Noc/Bpm (mm−1). (G) MS/BS (%). (H) Mineral apposition rate (μm/day). (I) Bone formation rate (μm3/μm2/day). (J) Representative images from von Kossa staining of the femurs at 6 weeks. (K and L) Serum osteocalcin levels (ng/ml) (K) and TRAP5b levels (units/liter) (L) as measured by ELISA. All results are presented as the mean ± SEM. *, P < 0.01.
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Fig. 2.Ex vivo μ and biomechanical analysis of the fifth lumbar vertebrae of ActRIIA–mFc-treated mice. Open bars represent VEH-treated mice, and filled bars represent ActRIIA–mFc-treated mice. (A) Tb BV/TV (%). (B) Trabecular number (mm−1). (C) TbTh (μm). (D) Representative three-dimensional μCT images of vertebrae from mice treated for 6 weeks with VEH or ActRIIA–mFc. (E) Vertebral failure load (N) from compression testing. (F) Energy-to-failure (N × nmm) from compression testing. All results are presented as the mean ± SEM. *, P < 0.01; +, P < 0.05.
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Fig. 3.ActRIIA–mFc treatment reverses trabecular bone loss in ovariectomized mice. OVX or SHAM mice were treated with ActRIIA–mFc (filled bars) or VEH (open bars) for a total of 12 weeks. In vivo pQCT assessment of trabecular bone density (mg/cm3) in the proximal tibia of OVX (A) and SHAM (B) mice was determined before dosing and after 4, 6, 8, and 12 weeks of treatment. (C) The Tb BV/TV (%) in OVX and SHAM mice was determined by ex vivo μCT analysis of the fifth lumbar vertebra. (D) Representative images of vertebrae are shown for each treatment group. (E) Vertebral failure load (N) determined by compression testing from OVX- and SHAM-treated mice. (F) Energy-to-failure (N × mm) from OVX and SHAM. All results are reported as the mean ± SEM. *, P < 0.01.
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Fig. 4.ActRIIA–mFc increases cortical bone volume and improves femoral strength. Cortical bone mass and strength was assessed in the femur of VEH-treated (open bars) and ActRIIA–mFc-treated (filled bars) mice by μCT after 12 weeks of treatment. (A) Representative cross-sectional images of the femoral diaphysis. (B) The cortical thickness (μm) at the diaphysis of OVX and SHAM mice. (C) Total cross-sectional area (mm2) of the femur in OVX and SHAM mice. (D) The failure load (N) was determined by three-point bending analysis of the femur for each group. (E) The energy-to-failure (N × mm) was also determined for each group. *, P ≤ 0.01.
Footnotes
- †To whom correspondence should be addressed. E-mail: spearsall{at}acceleronpharma.com
- © 2008 by The National Academy of Sciences of the USA
