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

• Applicant: Professor Dr. Klaus Aktories, since 11/2016
• Subject Area: Pharmacology ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2010 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 158454966

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.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Privatdozent Dr. Joachim Orth, until 10/2016