Stimulation of bone resorption by inflamed nasal mucosa, dermonecrotic toxin-containing conditioned medium from Pasteurella multocida, and purified dermonecrotic toxin from P. multocida

Kimman, Tjeerd G.; Löwik, C.W.G.M.; Wee-Pals, L. J. A. Van De; Thesingh, C. W.; Defize, P.; Kamp, E. M.; Bijvoet, O. L. M.

doi:10.1128/iai.55.9.2110-2116.1987

Cited by 46 publications

(23 citation statements)

References 20 publications

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“…Histologically, the lesions induced by B. bronchiseptica suggest impaired osteoblastic function (119), which contrasts with the histological picture of increased osteoclastic activity in animals exposed to PMT (discussed above). There is only one report of the effect of DNT on cultured bone, and its effects were not particularly striking (58). However, when added to the murine osteoblastic cell line MC3T3-E1 it caused changes in cellular architecture and potently inhibited (50% inhibitory concentration, 100 pg/ml) the osteoblasts' capacity to produce both alkaline phosphatase and collagen (45), an action that could seriously affect bone remodelling if replicated in vivo.…”

Section: The Capacity Of Bacteria and Their Products To Inhibit Bone mentioning

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: The Capacity Of Bacteria and Their Products To Inhibit Bone mentioning

confidence: 99%

Bacterially induced bone destruction: mechanisms and misconceptions

et al. 1996

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“…Some of these strains are toxigenic and produce a 146 kDa protein toxin (PMT) that acts in a highly mitogenic manner (Rozengurt et al ., 1990). In pigs, P. multocida causes atrophic rhinitis where PMT inhibits osteoblast activity and stimulates osteoclastic bone resorption at nasal turbinates and causes inflammation of the nasal mucosa (Kimman et al ., 1987). Humans are rarely affected but can suffer from local wound infections after animal bites, potentially leading to abscesses, septic arthritis, or occasionally to generalized infections.…”

Section: Introductionmentioning

confidence: 99%

Pasteurella multocida Toxin-induced Pim-1 expression disrupts suppressor of cytokine signalling (SOCS)-1 activity

Hildebrand¹,

Walker²,

Dalpke³

et al. 2010

Cellular Microbiology

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SummaryPasteurella multocida Toxin (PMT) is a mitogenic protein toxin that manipulates signal transduction cascades of mammalian host cells and upregulates Janus kinase (JAK) and signal transducers of transcription (STAT) activity. Here we show that in the presence of PMT, increased levels of suppressors of cytokine signalling-1 (SOCS-1) proteins significantly enhance STAT activity. This occurs via PMT-induced expression of the serine/ threonine kinase Pim-1 and subsequent threonine phosphorylation of SOCS-1. The ability of SOCS-1 to act as an E3 ubiquitin ligase is regulated by its phosphorylation status. Thus, the tyrosine kinase JAK2 cannot be marked for proteasomal degradation by threonine phosphorylated SOCS-1. Consequently, the expression levels of JAK2 are increased, eventually leading to hyperactivity of JAK2 and its target, the transcription factor STAT3. Eventually this causes increased anchorageindependent cell growth that correlates with the expression levels of SOCS-1. Interestingly, endogenous SOCS-1 production after Toll-like receptor activation also causes STAT3 hyperactivation. Thus we hypothesize that P. multocida Toxin alters host cell signalling using mechanisms that have so far only been known to be employed by oncogenic viral kinases to avoid host immune defence mechanisms.

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“…Bordetella bronchiseptica dermonecrotizing toxin (DNT) is a single chain polypeptide with a relative molecular mass of about 150000 [1,2]. The toxin is known to cause dermonecrotic lesions following intradermal injection in various laboratory animals and to be one of the causative agents of turbinate atrophy in swine atrophic rhinitis [3][4][5][6][7][8][9][10]. Horiguchi et al [11].…”

Section: Introductionmentioning

confidence: 99%

Bordetella bronchiseptica dermonecrotizing toxin stimulates protein synthesis in an osteoblastic clone, MC3T3-E1 cells

Horiguchi

1994

FEMS Microbiology Letters

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The effects of Bordetella bronchiseptica dermonecrotizing toxin on protein synthesis in an osteoblastic clone, MC3T3-E1 cells, were investigated. The rate of protein synthesis in the serum-starved cells was increased by the toxin after a latent period of about 4 h, and reached 2.5 times that of the control 24 h after addition of toxin. The toxin raised the level of protein synthesis even in actively proliferating cells. The stimulatory effect of the toxin on protein synthesis occurred earlier than other toxic events so far reported, such as the stimulation of DNA synthesis and the inhibition of osteoblastic differentiation, and was apparently dependent on the toxin concentrations over the range 0.05 ng ml-1 to 6.0 ng ml-1. Therefore, the stimulatory effect of the toxin on protein synthesis could be useful in determining the mode of action of the toxin.

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Stimulation of bone resorption by inflamed nasal mucosa, dermonecrotic toxin-containing conditioned medium from Pasteurella multocida, and purified dermonecrotic toxin from P. multocida

Cited by 46 publications

References 20 publications

Bacterially induced bone destruction: mechanisms and misconceptions

Bacterially induced bone destruction: mechanisms and misconceptions

Pasteurella multocida Toxin-induced Pim-1 expression disrupts suppressor of cytokine signalling (SOCS)-1 activity

Bordetella bronchiseptica dermonecrotizing toxin stimulates protein synthesis in an osteoblastic clone, MC3T3-E1 cells

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