Osseous effects of TGF-ß antibody treatment in a mouse model of severe Osteogenesis imperfecta.

• Applicant: Dr. Josephine T. Tauer
• Subject Area: Pediatric and Adolescent Medicine ; Endocrinology, Diabetology, Metabolism
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283054866

Osteogenesis imperfecta (OI), a genetic bone fragility disorder, is mainly caused by mutations in collagen type I encoding genes that interfere with the production of bone matrix by osteoblasts. At present, bisphosphonate therapy represents the standard of care of OI. But many pediatric patients with OI suffer fractures and bone deformations despite bisphosphonate therapy. More effective treatment approaches are thus needed. First results of a new treatment strategy were shown by TGF-ß antibody (AB) treatment of mouse models with mild forms of OI, resulting in improved bone mass and bone strength. However, it is not clear whether this treatment strategy also improves bone fragility in severe forms of OI. Therefore, we investigated TGF-ß-AB treatment in the new mouse model Col1a1Jrt/+, which has a severe OI phenotype. Starting at an age of 8 weeks we treated male Col1a1Jrt/+ mice by i.p. AB injections and investigated osseous effects after a treatment period of 8 weeks. The time period of this research grant was 12 month, starting November 2015 until October 2016. However, during the implementation of the animal experiments two problems occurred: 1. increased mortality rate of TGF-ß-AB treated mice; and 2. insufficient offspring of Col1a1Jrt/+ mice. The first problem could be solved by changing the application technique but not the second one. Due to insufficient offspring it is not possible to complete the research fellowship until October 2016. Since April 2016, offspring rate of the Col1a1Jrt/+ mice stabilizes. Therefore, we want to extend the research grant by 12 month to finish all interventions and to analyze all results.However, a first interim analysis of the generated results showed that an intervention directly on bone probably cannot achieve the desired effect of a significant improvement of the osseous phenotype. This may be due to the changes of administration or to the starting point of therapy. Therefore, we want to carry out two comparative experiments in addition: 1. use of female animals to determine whether AB administration is the reason for the limitations of the effect of TGF-ß -AB treatment on bone structures; and 2. test of a new therapeutic approach for stimulation of bone mass through stimulation of muscle mass by use of the muscle stimulator ACE 2494. To ensure comparability with TGF-ß-AB treatment, experimental setup and subsequent investigations of both comparative experiments are based on research grant.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Dr. Frank Thomas Rauch