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

成骨不全(OI)是一种遗传性骨脆性疾病，主要由I型胶原编码基因突变引起，I型胶原编码基因干扰成骨细胞产生骨基质。目前，双膦酸类药物治疗代表了OI的治疗标准。但许多患有OI的儿童患者尽管接受了双磷酸盐治疗，但仍会发生骨折和骨骼变形。因此，需要更有效的治疗方法。首次展示了一种新的治疗策略的结果，即用转化生长因子抗体(AB)治疗患有轻度OI的小鼠模型，从而改善骨量和骨强度。然而，目前尚不清楚这种治疗策略是否也能改善严重OI患者的骨脆性。因此，我们在具有严重OI表型的新小鼠模型Col1a1Jrt/+中研究了转化生长因子-β-AB的治疗。从8周龄开始，我们给雄性Col1a1Jrt/+小鼠进行了腹腔注射。AB注射，并在治疗8周后调查骨骼效应。这项研究资助的时间为12个月，从2015年11月到2016年10月。然而，在动物实验的实施过程中，出现了两个问题：1.转化生长因子-β-AB处理的小鼠死亡率增加；2.Col1a1Jrt/+小鼠后代不足。第一个问题可以通过改变应用技术来解决，但第二个问题不能。由于后代不足，要到2016年10月才能完成研究奖学金。自2016年4月以来，Col1a1Jrt/+小鼠的子代比率稳定。因此，我们希望将研究经费延长12个月，以完成所有干预并分析所有结果。然而，对产生的结果进行第一次中期分析表明，直接对骨骼进行干预可能无法达到显著改善骨表型的预期效果。这可能是由于给药方式的改变或治疗起点的改变。因此，我们还想进行两个对比实验：1.使用雌性动物来确定AB给药是否是导致转化生长因子-B-AB治疗对骨结构影响有限的原因；2.测试一种新的治疗方法，通过使用肌肉刺激物ACE 2494刺激肌肉块来刺激骨量。为了确保与转化生长因子-β-AB治疗的可比性，两个对比实验的实验设置和随后的调查都是基于研究拨款。

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.