Skeletal Response to Soluble Activin Receptor Type IIB in Mouse Models of Osteogenesis Imperfecta. (22nd June 2018)

• Record Type: Journal Article
• Authors: Jeong, Youngjae; Daghlas, Salah A; Xie, Yixia; Hulbert, Molly A; Pfeiffer, Ferris M; Dallas, Mark R; Omosule, Catherine L; Pearsall, R Scott; Dallas, Sarah L; Phillips, Charlotte L
• Is Part Of: Journal of bone and mineral research. Volume 33:Number 10(2018)
• Page Start: 1760
• Page End: 1772
• Publication Date: 2018-06-22
• Subjects: OSTEOGENESIS IMPERFECTA -- ANALYSIS/QUANTIFICATION OF BONE -- MYOSTATIN -- DECOY ACTIVIN RECEPTOR -- CELL/TISSUE SIGNALING; Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.3473
• Languages: English
• ISSNs: 0884-0431

Abstract

ABSTRACT: Osteogenesis imperfecta (OI) is a heritable connective tissue disorder primarily due to mutations in the type I collagen genes (COL1A1 and COL1A2), leading to compromised biomechanical integrity in type I collagen‐containing tissues such as bone. Bone is inherently mechanosensitive and thus responds and adapts to external stimuli, such as muscle mass and contractile strength, to alter its mass and shape. Myostatin, a member of the TGF‐β superfamily, signals through activin receptor type IIB to negatively regulate muscle fiber growth. Because of the positive impact of myostatin deficiency on bone mass, we utilized a soluble activin receptor type IIB‐mFc (sActRIIB‐mFc) fusion protein in two molecularly distinct OI mouse models ( G610C and oim ) and evaluated their bone properties. Wild‐type (WT), +/G610C, and oim/oim mice were treated from 2 to 4 months of age with either vehicle (Tris‐buffered saline) or sActRIIB‐mFc (10 mg/kg). Femurs of sActRIIB‐mFc‐treated mice exhibited increased trabecular bone volume regardless of genotype, whereas the cortical bone microarchitecture and biomechanical strength were only improved in WT and +/G610C mice. Dynamic histomorphometric analyses suggest the improved cortical bone geometry and biomechanical integrity reflect an anabolic effect due to increased mineral apposition and bone formation rates, whereas static histomorphometric analyses supported sActRIIB‐mFc treatment also having an anti‐catabolic impact with decreased osteoclast number per bone surface on trabecular bone regardless of sex and genotype. Together, our data suggest that sActRIIB‐mFc may provide a new therapeutic direction to improve both bone and muscle properties in OI. © 2018 American Society for Bone and Mineral Research.