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Activin Receptor-Based Therapies for Musculoskeletal Disease
Sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Disease -- 1R01AR062074-04
The overall goal of this project is to investigate the role of the myostatin/activin signaling pathway in regulating bone formation and bone density, as well as evaluating the therapeutic efficacy of modulating this pathway to treat age-related muscle and bone loss. Part of this project will be carried out by Emily Germain-Lee (co-investigator) as a subaward to the Kennedy Krieger Institute. This part of the project will be carried out as a collaboration with investigators at the Johns Hopkins University School of Medicine [Douglas DiGirolamo (Department of Orthopaedic Surgery) and Se-Jin Lee, (Department of Molecular Biology and Genetics)] and will focus on the translational studies investigating the potential beneficial effects of targeting this signaling pathway in a mouse model of age-related muscle and bone mass, as described below in this excerpt from Aim 2 of the grant.
The final series of studies will test the ability of the biologics to improve bone and muscle mass in aged mice. As discussed in the background, there is an urgent need to develop more effective therapies for combating sarcopenia and osteopenia in the elderly. Therefore, the ultimate payoff of our project will be the development of safe and effective activin receptor-based therapies for treating age-related frailty associated with reduced bone and muscle mass. Knowledge of age-related changes in murine bone and muscle morphology is critical for interpreting the musculoskeletal response to our proposed pharmacologic interventions in mice, particularly since the different biologics appear to have different anabolic profiles in muscle and bone. Fortunately, detailed studies by Bouxsein's group have documented the features of bone loss in C57BL-6 mice, the same background strain as the mutant and wild-type mice described in our experimental strategy. In these studies, age-related decreases in trabecular BV/TV occurred rapidly in females between two and six months of age. By contrast, cortical thickness increased markedly from one to three months of age and was largely maintained thereafter.
Previous studies of muscle loss in aging mice provide additional baseline information. In this study, the percentage of muscle mass lost in myostatin deficient C57BL-6 mice with age was remarkably similar in both WT and KO groups. However, the senescent KO mice maintained more muscle mass compared to WT (106.3±6.3 vs 234.9±12.4 mg, p<0.001). Based on the results from these previous studies, we will use approximately 30-month-old C57/BL6 mice (Harlan), the same background as each of our genetic mouse models. This age is above the reported median age for this strain (age at which 50 percent of the mice have died) and represents the human equivalent of approximately 90 years of age. Mice of this age have approximately 40 percent less muscle mass and concomitant reductions in BMD compared to 16-week old, young adult mice. We believe this model represents the best mouse approximation of the type of "worst case scenario" that clinicians might encounter when a 90+ year old woman presents with severe muscle wasting and frailty fractures; thus a highly relevant model for testing our biologics.
The prioritization of the biologics for testing will be based on the results of our dose and timing studies in young adult wild-type mice described above. Thus, for this model of severe osteopenia and sarcopenia, we will select the biologic that exhibits the best combined anabolic profile in bone and muscle. Based upon our preliminary data, it is likely that we will begin with ACVR2B/Fc, to be administered according to the same four-week injection protocol we have already performed. However, in addition to the magnitude of anabolic response, particular attention will be paid to the results of mechanical testing. For instance, it is possible that ACVR2/Fc, despite less overall muscle and bone growth, would actually be more beneficial mechanically because of its ability to induce cortical growth. Following the course of injections, mice will be euthanized, and muscles, femora and calvaria will be harvested for analysis as described for the young adult mice above.