Involvement of heterotrimeric G proteins in bone atrophy caused by Pasteurella multocida toxin

多杀性巴氏杆菌毒素（PMT）可引起猪进行性萎缩性鼻炎，其特征是鼻甲骨的降解。PMT的分子机制的阐明使我们能够确定毒素对骨细胞的分化和功能的显着影响。因此，PMT诱导的萎缩性鼻炎的病理生理学基础可以进行研究。在接下来的时间里，成功建立的方法将用于完成PMT对骨组织影响的一致的整体图片。此外，还将进一步研究毒素对骨细胞作用的病理生理学后果。功能重要的骨细胞是骨形成或消耗成骨细胞和破骨细胞。骨细胞在骨细胞中所占比例最大，能够通过多种相互作用调节成骨细胞和破骨细胞的活性。PMT是否也影响骨细胞，从而导致萎缩性鼻炎的表型，还有待进一步研究。前成骨细胞和成骨细胞不仅对骨组织的发育至关重要。在过去的几年里，已经建立了发育中的免疫细胞和骨细胞之间的强烈相互作用。我们实验室的初步实验已经显示PMT抑制基质细胞或成骨细胞中的B细胞刺激因子。应进一步研究这种影响。这是特别令人感兴趣的，因为已经描述了PMT或多杀性巴氏杆菌感染对抗体形成的抑制作用。进行性骨化性纤维发育不良是一种罕见的疾病，它通过异位骨化导致功能性瘫痪。Alk2（一种骨形态发生蛋白（BMP）受体）的突变已被确定为致病机制。这些突变导致下游信号转导途径的激活，进而导致成骨细胞生成。PMT将被用作一个模型，以证明异位成骨细胞生成可以通过激活异源三聚体G蛋白来抑制。这可能导致一种新的治疗方法的定义。

Pasteurella multocida toxin (PMT) induces the so-called progressive atrophic Rhinitis in pigs, which is characterized by the degradation of the turbinate bone. The elucidation of the molecular mechanism of PMT has allowed us defining significant effects of the toxin on the differentiation and function of bone cells. The pathophysiological basis of the PMT-induced atrophic rhinitis can therefore be investigated.In the following period, the successfully established methods will be used to complete a consistent overall picture of the effects of PMT on the bone tissue. In addition, further pathophysiological consequences of the toxin, mediated by its effects on bone cells, will be studied.Functionally important bone cells are bone forming or depleting osteoblasts and osteoclasts. The osteocytes, which account for the largest proportion of bone cells numerically, are able to regulate the activity of osteoblasts and osteoclasts through a variety of interactions. It should be investigated whether PMT also affects osteocytes to contribute to the phenotype of the atrophic rhinitis. Pre-osteoblasts and osteoblasts are not only crucial for the development of bone tissue. Over the last few years a strong cross-talk between developing immune cells and bone cells has been established. Initial experiments in our lab have already shown an inhibition of B cell-stimulating factors in stromal cells or osteoblasts by PMT. This effect should be further investigated. This is of particular interest, because a suppressive effect of PMT or a P. multocida infection on antibody formation has been described. So far the pathophysiological bases was enigmatic.The fibrodysplasia ossificans progressiva is a rare disease that leads to heterotopic ossification of soft tissue leading to a functional paralysis. Mutations in Alk2, a bone morphogenetic protein (BMP) receptor have been identified as the causative mechanism. These mutations lead to an activation of the downstream signal transduction pathway and in turn to an osteoblastogenesis. PMT will be used as a model to demonstrate that heterotopic osteoblastogenesis can be inhibited by activation of heterotrimeric G proteins. This could lead to the definition of a new therapeutic approach.