Skeletal Response to Soluble Activin Receptor Type IIB in Mouse Models of Osteogenesis Imperfecta

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.

Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

“…Decorin aberrant presence may also contribute to another OI feature, as suggested by its annotating GO terms: “skeletal muscle tissue development” and “response to mechanical stimulus”, from differentiation and development and cytoskeleton and nucleoskeleton organization clusters, respectively. Given the interdependence of bone and skeletal muscle development and function, OI patients show an altered skeletal muscle physiology [ 70 ]. Many OI patients report intolerance to physical activity, fatigue, and muscle weakness, and, in some cases, these phenomena are so severe that they are valued as symptoms of the disease [ 16 ].…”

“…Many OI patients report intolerance to physical activity, fatigue, and muscle weakness, and, in some cases, these phenomena are so severe that they are valued as symptoms of the disease [ 16 ]. Despite it not being the main collagenic component in muscle ECM, mutant collagen type I is thought to have a detrimental effect also on muscle-ECM properties and function [ 70 ]. Indeed, OI muscle deficiency does not merely result from motor difficulties and inactivity; it likely depends also on the incapability of muscle connective tissue to respond to mechanical stimuli during contractile force transmission.…”

Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight

“…Moreover, because this decoy receptor can block not only MSTN but also activin A, systemic administration of ACVR2B/Fc can also lead to significant increases in bone density ( 18 – 20 ). The dual ability of ACVR2B/Fc to promote muscle growth and to increase bone density has suggested the possibility that this therapeutic strategy may be particularly useful to combat simultaneously comorbid muscle and bone loss, and indeed, this strategy has been shown to be effective in a mouse model of osteogenesis imperfecta, which is characterized by both muscle atrophy and bone fragility ( 21 , 22 ).…”

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research

“…A soluble activin receptor 2B that inhibits both myostatin and activin A led to a marked increase in muscle and bone mass in oim mice . A slightly different soluble activin receptor 2B had similarly beneficial effects on muscles and bones in oim and G610C mice . Inhibition of myostatin and activin A warrants further exploration as novel treatment approaches in OI.…”

“…(124) A slightly different soluble activin receptor 2B had similarly beneficial effects on muscles and bones in oim and G610C mice. (125,126) Inhibition of myostatin and activin A warrants further exploration as novel treatment approaches in OI.…”