Hard labour: bacterial infection of the skeleton

doi:10.1016/j.tim.2003.10.005

Trends in Microbiology

Volume 11, Issue 12, December 2003, Pages 570-577

https://doi.org/10.1016/j.tim.2003.10.005 Get rights and content

Abstract

The skeleton is the largest mammalian organ system, containing a myriad of blood vessels, tissue surfaces and bone cells for bacterial colonization. Although rock-like, the skeleton is a dynamic structure that is undergoing constant remodelling. This is the result of the opposing actions of two key cells: the osteoblast, which produces bone, and the osteoclast, a multinucleate cell that ‘eats’ bone. It is not generally realized that the most prevalent chronic bacterial diseases of Homo sapiens afflict the skeleton. Several pathogens, and members of the normal microbiota, have evolved specific cellular and molecular mechanisms for invading bone, including its cellular constituents. The host cellular pathways that are activated and lead to destruction or loss of the bone matrix will be described.

Section snippets

Bone: a dynamic organ

The rock-like solidity of the skeleton belies a cell-rich, metabolically active, organ system that is in a state of dynamic equilibrium. Bone, a fibre-reinforced composite material, is produced by a mesenchymal cell, the osteoblast, which lays down the organic matrix and aids in its calcification. A separate myeloid cell, the multinucleate osteoclast, controls the removal of this matrix. It is the antithetical actions of these two cells that make bone the dynamic tissue that it is (Figure 2).

How could bacteria cause bone destruction?

To place the literature of bacterial-induced bone resorption in context, it is helpful to address the question; how could bacteria cause bone destruction? It is proposed that at least five mechanisms exist (Figure 4), and that bacteria might use one or all of them to produce skeletal damage. The ability to use these different destructive mechanisms depends on the nature of the infection and how close the contact is between the bone and the infecting bacteria. Direct destruction of the inorganic

Actions of cell-surface or exported bacterial macromolecules on bone remodelling

Initial attempts to understand how bacteria could drive the process of bone resorption concentrated on known virulence factors, particularly lipopolysaccharide (LPS) and peptidoglycan. In the past decade, increasing numbers of bacterial components have been identified as being capable of inducing bone resorption using rodent bone as a target tissue (Table 2). These include molecules as diverse as LPS, lipopeptides, molecular chaperones, porins, CpG oligonucleotides and P. multocida toxin (PMT).

Bacterial-induced bone resorption in vivo

Assessing bacterial-induced bone resorption in cell or explant culture is an obvious simplification of the real-life situation, and increasingly workers studying bone destruction are using inbred mice that permit the genetics of susceptibility to bone infection to be studied and enable growing numbers of transgenic mouse strains to be used for hypothesis testing [31].

P. gingivalis is strongly associated as the causative agent of adult periodontitis [32]. To assess susceptibility to bone loss,

Bacterial invasion of bone cells

A new paradigm in bone infection is the internalization of bacteria by osteoblasts, the first example of which was reported by Hudson et al. [52]. It is now clear that several bacteria that cause osteomyelitis and/or osteitis are taken up by bone cells. These include S. aureus [52], S. epidermidis (B. Henderson and S.P. Nair, unpublished), Salmonella [53] and Mycobacterium bovis (BCG) [54]. It has been hypothesized that bacterial internalization offers protection from the host immune system and

Treatment of bone infection

Osteomyelitis and orthopaedic implant infections are notoriously difficult to treat with antibiotics [3] and the enormous prevalence of periodontitis rules out the general use of antibiotics for this disease. Novel treatments for organisms infecting bone include immunization against the organism of interest. This is of value when single organisms are involved, which is not the case with oral bacterial diseases. An alternative is to target the host systems driving bone resorption. Administration

Conclusions

The past five years have seen major advances in our understanding of the cytokine networks (RANKL, RANK, OPG and TRAIL) controlling osteoblast–osteoclast interactions, and there is growing evidence that bacteria have evolved mechanisms for the modulation of these and associated bone-cell communication networks. A growing number of bacterial components involved in immune modulation are also able to promote formation of osteoclasts; the latest is CpG DNA, which is reported to interact with

Acknowledgements

We acknowledge the financial support of the Arthritis Research Campaign (Programme Grant HO600)and thank Derren Ready for Figure 1.

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Trends in Microbiology

Hard labour: bacterial infection of the skeleton

Abstract

Section snippets

Bone: a dynamic organ

How could bacteria cause bone destruction?

Actions of cell-surface or exported bacterial macromolecules on bone remodelling

Bacterial-induced bone resorption in vivo

Bacterial invasion of bone cells

Treatment of bone infection

Conclusions

Acknowledgements

J. Hosp. Infect.

Vet. Microbiol.

Cytokine Growth Factor Rev.

J. Biol. Chem.

Int. J. Med. Microbiol.

Curr. Opin. Immunol.

FEMS Immunol. Med. Microbiol.

Am. J. Pathol.

Bone

Trends Microbiol.

FEMS Microbiol. Lett.

Microb. Pathog.

J. Biol. Chem.

Oral Health in America

A Report of the Surgeon General

Epidemiology of periodontal disease: a review and clinical perspectives

J. Int. Acad. Periodontol.

Pathophysiology of chronic bacterial osteomyelitis. Why do antibiotics fail so often?

Postgrad. Med. J.

Role of osteoblasts in hormonal control of bone resorption – a hypothesis

Calcif. Tissue Int.

Ecological basis for dental caries

Minireview – bacterially-induced bone destruction: mechanisms and misconceptions

Infect. Immun.

Effect of MALP-2, a lipopeptide from Mycoplasma fermentans, on bone resorption in vitro

Infect. Immun.

Comparison of the osteolytic activity of surface-associated proteins of bacteria implicated in periodontal disease

Oral Dis.

Effect of Pasteurella multocida toxin on bone resorption in vitro

Infect. Immun.

Molecular pathogenicity of the oral opportunistic pathogen Actinobacillus actinomycetemcomitans

Annu. Rev. Microbiol.

Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its p55 receptor

J. Clin. Invest.

Bacteria induce osteoclastogenesis via an osteoblast-independent pathway

Infect. Immun.

Lipopolysaccharide supports survival and fusion of preosteoclasts independent of TNFα, IL-1 and RANKL

J. Cell. Physiol.

Segregation of TRAF6-mediated signalling pathways clarifies its role in osteoclastogenesis

EMBO J.

Inhibition of osteoblastic cell differentiation by lipopolysaccharide extract from Porphyromonas gingivalis

Infect. Immun.

Gene expression of osteoclast differentiation factor is induced by lipopolysaccharide in mouse osteoblasts via toll-like receptors

J. Immunol.

Cot/Tpl2 is essential for RANKL induction by lipid A in osteoblasts

J. Dent. Res.

Impaired bone resorption by lipopolysaccharide in vivo in mice deficient in the prostaglandin E receptor EP4 subtype

Infect. Immun.