Effects of purified <i>Pasteurella multocida</i> dermonecrotoxin on cartilage and bone of the nasal ventral conchae of the piglet

Martineau-Doizé, B; Frantz, J C; Martineau, G. P.

doi:10.1002/ar.1092280302

Cited by 18 publications

(10 citation statements)

References 20 publications

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“…It is assumed that the mitogenic activity of PMT is related to its potent ability to promote bone resorption. In experimental studies in which PMT has been administered to experimental animals, bone resorption was associated with an increased number of osteoclasts in affected bones (1,14,21,73,74). A surprising finding was that intraperitoneal injection of PMT resulted in increased osteoclast density and bone loss both in the maxillofacial skeleton and in the appendicular skeleton of rats (73).…”

Section: Fig 3 the Possible Points Of Interaction Between Osteolytimentioning

confidence: 99%

Bacterially induced bone destruction: mechanisms and misconceptions

et al. 1996

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Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and replacement of bone matrix. At the present time, it is not possible to define a general mechanism by which bacteria promote loss of bone matrix. Many bacteria are capable of stimulating bone matrix loss, and the information available would suggest that each organism possesses different factors which interact with bone in different ways. With the rapid increase in antibiotic resistance, particularly with Staphylococcus aureus and M. tuberculosis, organisms responsible for much bone pathology in developed countries only two generations ago, we would urge that much greater attention should be focused on the problem of bacterially induced bone remodelling in order to define pathogenetic mechanisms which could be therapeutic targets for the development of new treatment modalities.

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Section: Fig 3 the Possible Points Of Interaction Between Osteolytimentioning

confidence: 99%

Bacterially induced bone destruction: mechanisms and misconceptions

et al. 1996

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“…Inoculation of PMT alone is sufficient to generate all symptoms of atrophic rhinitis in animals [6]. Bone tissue is constantly rebuilt by the action of osteoblasts and osteoclasts [7].…”

Section: Introductionmentioning

confidence: 99%

Pasteurella Multocida Toxin Prevents Osteoblast Differentiation by Transactivation of the MAP-Kinase Cascade via the Gαq/11 - p63RhoGEF - RhoA Axis

et al. 2013

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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.

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“…Type D and A strains for example are associated with upper respiratory tract infections in pigs and toxigenic strains expressing the Pasteurella multocida Toxin (PMT) cause porcine atrophic rhinitis [2]. This disease is characterized by an atrophy of the nasal ventral conchae bones and a shortening or distortion of the snout [3]. After purification of the toxin in the late 1980s, it was shown that the purified toxin alone was sufficient to induce bone lesions and thus must be the causative agent of porcine atrophic rhinitis [4,5,6].…”

Section: Introductionmentioning

confidence: 99%

Signaling Cascades of Pasteurella multocida Toxin in Immune Evasion

Kubatzky

Kloos

Hildebrand

2013

Toxins

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Pasteurella multocida toxin (PMT) is a protein toxin found in toxigenic strains of Pasteurella multocida. PMT is the causative agent for atrophic rhinitis in pigs, a disease characterized by loss of nasal turbinate bones due to an inhibition of osteoblast function and an increase in osteoclast activity and numbers. Apart from this, PMT acts as a strong mitogen, protects from apoptosis and has an impact on the differentiation and function of immune cells. Many signaling pathways have been elucidated, however, the effect of these signaling cascades as a means to subvert the host’s immune system are just beginning to unravel.

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Effects of purified Pasteurella multocida dermonecrotoxin on cartilage and bone of the nasal ventral conchae of the piglet

Cited by 18 publications

References 20 publications

Bacterially induced bone destruction: mechanisms and misconceptions

Bacterially induced bone destruction: mechanisms and misconceptions

Pasteurella Multocida Toxin Prevents Osteoblast Differentiation by Transactivation of the MAP-Kinase Cascade via the Gαq/11 - p63RhoGEF - RhoA Axis

Signaling Cascades of Pasteurella multocida Toxin in Immune Evasion

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