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Abstract
The 146-kDa Pasteurella multocida toxin (PMT) is the main virulence factor to induce P. multocida-associated progressive atrophic rhinitis in various animals. PMT leads to a destruction of nasal turbinate bones implicating an effect of the toxin on osteoblasts and/or osteoclasts. The toxin induces constitutive activation of Gα proteins of the Gq/11-, G12/13- and Gi-family by deamidating an essential glutamine residue. To study the PMT effect on bone cells, we used primary osteoblasts derived from rat calvariae and stromal ST-2 cells as differentiation model. As marker of functional osteoblasts the expression and activity of alkaline phosphatase, formation of mineralization nodules or expression of specific transcription factors as osterix was determined. Here, we show that the toxin inhibits differentiation and/or function of osteoblasts by activation of Gαq/11. Subsequently, Gαq/11 activates RhoA via p63RhoGEF, which specifically interacts with Gαq/11 but not with other G proteins like Gα12/13 and Gαi. Activated RhoA transactivates the mitogen-activated protein (MAP) kinase cascade via Rho kinase, involving Ras, MEK and ERK, resulting in inhibition of osteoblast differentiation. PMT-induced inhibition of differentiation was selective for the osteoblast lineage as adipocyte-like differentiation of ST-2 cells was not hampered. The present work provides novel insights, how the bacterial toxin PMT can control osteoblastic development by activating heterotrimeric G proteins of the Gαq/11-family and is a molecular pathogenetic basis for understanding the role of the toxin in bone loss during progressive atrophic rhinitis induced by Pasteurella multocida.
Highlights
Bone tissue is a common target for bacterial infections
One induced syndrome is atrophic rhinitis, which is a form of osteopenia, mainly characterized by facial distortion due to degradation of nasal turbinate bones
We demonstrate the direct action of Pasteurella multocida toxin (PMT) on osteoblasts and osteoblast-like cells and as a consequence inhibition of osteoblastic differentiation
Summary
Bone tissue is a common target for bacterial infections. Diseases like caries, periodontitis or osteomyelitis are due to infections by Streptococcus mutans, Actinobacillus actinomycetemcomitans or Staphylococcus aureus inter alia. The mechanism of bacterial-induced bone damage may be caused by factors released from pathogens, which interact with bone matrix or affect bone cells, or by bacteria which directly invade bone cells to initiate pathological changes [1]. As a commensal P. multocida is found mainly in the nasal/pharyngeal space of domesticated and wild animals and is frequently isolated from cat and dog bites [2]. P. multocida is directly or as a supportive factor connected to several diseases like haemorrhagic septicaemia in hoofed animals, avian cholera or snuffles in rabbits [3]. Atrophic rhinitis is characterized by drastic degeneration of nasal turbinate bones, leading to a shortening and/or twisting of the snout accompanied by growth retardation of young pigs. Rabbits, wild pigs and cattle show atrophic rhinitis-like symptoms [3]
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