PurifiedPasteurella multocida protein toxin reduces acid phosphatase-positive osteoclasts in the ventral nasal concha of gnotobiotic pigs

Ackermann, Mark R.; Adams, D. A.; Gerken, L; Beckman, Matthew J.; Rimler, R. B.

doi:10.1007/bf00571336

Cited by 10 publications

(3 citation statements)

References 14 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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“…However, others have indicated a decrease in osteoclast numbers. ( 8‐11 ) Furthermore, co‐culture experiments using chick cells have suggested that the effects of PMT on osteoclasts may be mediated by osteoblastic cells. ( 12 ) PMT has also been shown to stimulate DNA synthesis in some, but not all osteoblastic, cell lines and to reduce the levels of alkaline phosphatase activity and type I collagen synthesis.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Osteoblast Differentiation by Pasteurella Multocida Toxin (PMT): A Role for Rho GTPase in Bone Formation

Harmey

Stenbeck

Nobes

et al. 2004

Journal of Bone and Mineral Research

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The role of the Rho-Rho kinase signaling pathway on osteoblast differentiation was investigated using primary mouse calvarial cells. The bacterial toxin PMT inhibited, whereas Rho-ROK inhibitors stimulated, osteoblast differentiation and bone nodule formation. These effects correlated with altered BMP-2 and -4 expression. These data show the importance of Rho-ROK signaling in osteoblast differentiation and bone formation. Introduction:The signal transduction pathways controlling osteoblast differentiation are not well understood. In this study, we used Pasteurella multocida toxin (PMT), a unique bacterial toxin that activates the small GTPase Rho, and specific Rho inhibitors to investigate the role of Rho in osteoblast differentiation and bone formation in vitro. Materials and Methods: Primary mouse calvarial osteoblast cultures were used to investigate the effects of recombinant PMT and Rho-Rho kinase (ROK) inhibitors on osteoblast differentiation and bone nodule formation. Osteoblast gene expression was analyzed using Northern blot and RT-PCR, and actin rearrangements were visualized after phalloidin staining and confocal microscopy. Results: PMT stimulated the proliferation of primary mouse calvarial cells and markedly inhibited the differentiation of osteoblast precursors to bone nodules with a concomitant inhibition of osteoblastic marker gene expression. There was no apparent causal relationship between the stimulation of proliferation and inhibition of differentiation. PMT caused cytoskeletal rearrangements because of activation of Rho, and the inhibition of bone nodules was completely reversed by the Rho inhibitor C3 transferase and partly reversed by inhibitors of the Rho effector, ROK. Interestingly, Rho and ROK inhibitors alone potently stimulated osteoblast differentiation, gene expression, and bone nodule formation. Finally, PMT inhibited, whereas ROK inhibitors stimulated, bone morphogenetic protein (BMP)-2 and -4 mRNA expression, providing a possible mechanism for their effects on bone nodule formation. Conclusions: These results show that PMT inhibits osteoblast differentiation through a mechanism involving the Rho-ROK pathway and that this pathway is an important negative regulator of osteoblast differentiation. Conversely, ROK inhibitors stimulate osteoblast differentiation and may be potentially useful as anabolic agents for bone.

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“…Thus, measurements of NTx in serum are regarded as one of the most reliable indicators of bone resorption (Watts, 1999). In contrast to the numerous markers that have been used for human studies, only a few of these parameters have been used for measurement in pigs in vivo (Pointillart et al., 1991; 2000; Ackermann et al., 1993; Bollen et al., 1997). Most of these measurements were limited to single samples and repeated measurements are reported only for NTx measurements in the urine of growing minipigs kept in metabolic cages (Bollen et al., 1997).…”

Section: Introductionmentioning

confidence: 99%

Comparison of Blood Markers for the Longitudinal Monitoring of Osteoclastic Activity in the Pig

Weiler

Finsler

Wehr

et al. 2001

Journal of Veterinary Medicine Series A

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In the present study the osteoclast activity was monitored longitudinally in porcine blood samples by measuring the tartrate-resistant acidic phosphatase (TRAP) activity with several methods described for human samples. These methods differed in their specificity for bone-specific TRAP and in their practicability. The validity of TRAP measurements was evaluated by comparison with the peripheral concentrations of the N-terminal fragments of type I collagen with attached cross-links (NTx), a highly bone-specific parameter of bone collagen degradation, using a commercially available test kit developed for human samples. On selected days urine samples were collected for the determination of pyridinium cross-links. The determinations of cross-links in urine were normalized for the creatinine concentrations. However, they were not related to fluoride-sensitive TRAP (fsTRAP) and NTx measurements in serum. The fsTRAP activity in serum, which is assumed to be highly bone-specific, was highly correlated with the NTx concentrations in serum under different experimental conditions. As measurements in blood may be more easily standardized than those in urine, fsTRAP measurements in serum seem to be a highly practicable method to characterize osteoclastic activity in the pig.

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PurifiedPasteurella multocida protein toxin reduces acid phosphatase-positive osteoclasts in the ventral nasal concha of gnotobiotic pigs

Cited by 10 publications

References 14 publications

Bacterially induced bone destruction: mechanisms and misconceptions

Bacterially induced bone destruction: mechanisms and misconceptions

Regulation of Osteoblast Differentiation by Pasteurella Multocida Toxin (PMT): A Role for Rho GTPase in Bone Formation

Comparison of Blood Markers for the Longitudinal Monitoring of Osteoclastic Activity in the Pig

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