The role of myostatin deficiency in the development and biomechanical integrity of offspring bone

Abstract

Osteogenesis imperfecta (OI) is a genetic bone disorder primarily caused by mutations to the genes for type I collagen, a major structural protein found in bone. There have been over 1,500 different mutations described that cause OI which lead to bone deformity, fragility, scoliosis, and increased fracture incidence. There is no cure for OI and treatment strategies remain limited. It is known that bone naturally responds to the forces it encounters from muscle loading by remodeling its structure to withstand these forces. We hypothesized that increasing muscle mass in a mouse model of osteogenesis imperfecta (oim) would be a therapeutic target to improve bone quality and strength. To test this hypothesis, a mouse model with inherently large muscles due to a deficiency in a protein called myostatin was bred to the oim mouse model. Our findings demonstrated that increased muscle mass in the oim mouse was able to alter the bone microarchitecture and mineral composition to increase the overall biomechanical strength of the compromised oim bone. This data supports that inhibition of myostatin is a novel therapeutic target for increasing both muscle mass and bone strength, and our findings demonstrate the potential of myostatin inhibition as a therapeutic approach to treat OI. Additionally, my research has explored maternal factors contributing to offspring bone development, maturation, and biomechanical integrity. During fetal development, changes in the uterine environment can have effects on offspring bone quality that persist throughout life. The focus of the second half of my research was to better understand the role of myostatin, a regulator of muscle mass, in the uterine environment and its impact on the muscle and bone health of adult offspring. Previous research with mice has shown that decreasing myostatin in the maternal uterine environment during development causes offspring to have larger muscles as adults. In a separate study, my research demonstrates that the decrease of maternal myostatin during fetal development also increases bone strength of adult wildtype offspring. Understanding the factors within the uterine environment that contribute to offspring bone integrity may provide potential therapeutic targets for increasing bone quality of OI patients in utero, which would persist throughout their lifetime. Our results have shown that mice carrying the oim mutation and exposed to a decrease of myostatin in the uterine environment during development have a 16% increase in biomechanical strength as adults. To explore the critical time point when maternal myostatin programs offspring bone integrity, I performed embryo transfers using the oim mouse model and transferring embryos into recipient female dams with a deficiency in myostatin. Taken together, my data demonstrates that the decrease of myostatin in the uterine environment improves the skeletal integrity of adult mice and further, that inhibiting myostatin in utero may provide a new therapeutic window for treating OI.