1887

Abstract

is the major pathogen among the staphylococci and the most common cause of bone infections. These infections are mainly characterized by bone destruction and inflammation, and are often debilitating and very difficult to treat. Previously we demonstrated that protein A (SpA) can bind to osteoblasts, which results in inhibition of osteoblast proliferation and mineralization, apoptosis, and activation of osteoclasts. In this study we used small interfering RNA (siRNA) to demonstrate that osteoblast tumour necrosis factor receptor-1 (TNFR-1) is responsible for the recognition of and binding to SpA. TNFR-1 binding to SpA results in the activation of nuclear factor kappa B (NFκB). In turn, NFκB translocates to the nucleus of the osteoblast, which leads to release of interleukin 6 (IL-6). Silencing TNFR-1 in osteoblasts or disruption of the gene in prevented both NFκB activation and IL-6 release. As well as playing a key role in proinflammatory reactions, IL-6 is also an important osteotropic factor. Release of IL-6 from osteoblasts results in the activation of the bone-resorbing cells, the osteoclasts. Consistent with our results described above, both silencing TNFR-1 in osteoblasts and disruption of in prevented osteoclast activation. These studies are the first to demonstrate the importance of the TNFR-1–SpA interaction in bone infection, and may help explain the mechanism through which osteoclasts become overactivated, leading to bone destruction. Anti-inflammatory drug therapy could be used either alone or in conjunction with antibiotics to treat osteomyelitis or for prophylaxis in high-risk patients.

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2013-01-01
2019-09-15
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References

  1. Ahmed S. , Meghji S. , Williams R. J. , Henderson B. , Brock J. H. , Nair S. P. . ( 2001; ). Staphylococcus aureus fibronectin binding proteins are essential for internalization by osteoblasts but do not account for differences in intracellular levels of bacteria. . Infect Immun 69:, 2872–2877. [CrossRef] [PubMed]
    [Google Scholar]
  2. Berendt T. , Byren I. . ( 2004; ). Bone and joint infection. . Clin Med 4:, 510–518.[PubMed] [CrossRef]
    [Google Scholar]
  3. Bu R. , Borysenko C. W. , Li Y. , Cao L. , Sabokbar A. , Blair H. C. . ( 2003; ). Expression and function of TNF-family proteins and receptors in human osteoblasts. . Bone 33:, 760–770. [CrossRef] [PubMed]
    [Google Scholar]
  4. Carmody R. J. , Chen Y. H. . ( 2007; ). Nuclear factor-κB: activation and regulation during Toll-like receptor signaling. . Cell Mol Immunol 4:, 31–41.[PubMed]
    [Google Scholar]
  5. Clarke B. . ( 2008; ). Normal bone anatomy and physiology. . Clin J Am Soc Nephrol 3: (Suppl. 3), S131–S139. [CrossRef] [PubMed]
    [Google Scholar]
  6. Claro T. , Widaa A. , O’Seaghdha M. , Miajlovic H. , Foster T. J. , O’Brien F. J. , Kerrigan S. W. . ( 2011; ). Staphylococcus aureus protein A binds to osteoblasts and triggers signals that weaken bone in osteomyelitis. . PLoS ONE 6:, e18748. [CrossRef] [PubMed]
    [Google Scholar]
  7. Duthie E. S. , Lorenz L. L. . ( 1952; ). Staphylococcal coagulase; mode of action and antigenicity. . J Gen Microbiol 6:, 95–107. [CrossRef] [PubMed]
    [Google Scholar]
  8. Edwards C. J. , Williams E. . ( 2010; ). The role of interleukin-6 in rheumatoid arthritis-associated osteoporosis. . Osteoporos Int 21:, 1287–1293. [CrossRef] [PubMed]
    [Google Scholar]
  9. Eriksen E. F. . ( 2010; ). Cellular mechanisms of bone remodeling. . Rev Endocr Metab Disord 11:, 219–227. [CrossRef] [PubMed]
    [Google Scholar]
  10. Foster T. J. . ( 2009; ). Colonization and infection of the human host by staphylococci: adhesion, survival and immune evasion. . Vet Dermatol 20:, 456–470. [CrossRef] [PubMed]
    [Google Scholar]
  11. García-Alvarez F. , Navarro-Zorraquino M. , Castro A. , Grasa J. M. , Pastor C. , Monzón M. , Martínez A. , García-Alvarez I. , Castillo J. , Lozano R. . ( 2009; ). Effect of age on cytokine response in an experimental model of osteomyelitis. . Biogerontology 10:, 649–658. [CrossRef] [PubMed]
    [Google Scholar]
  12. Gómez M. I. , O’Seaghdha M. , Magargee M. , Foster T. J. , Prince A. S. . ( 2006; ). Staphylococcus aureus protein A activates TNFR1 signaling through conserved IgG binding domains. . J Biol Chem 281:, 20190–20196. [CrossRef] [PubMed]
    [Google Scholar]
  13. Gómez M. I. , Seaghdha M. O. , Prince A. S. . ( 2007; ). Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling. . EMBO J 26:, 701–709. [CrossRef] [PubMed]
    [Google Scholar]
  14. Guicciardi M. E. , Gores G. J. . ( 2009; ). Life and death by death receptors. . FASEB J 23:, 1625–1637. [CrossRef] [PubMed]
    [Google Scholar]
  15. Hertzén E. , Johansson L. , Wallin R. , Schmidt H. , Kroll M. , Rehn A. P. , Kotb M. , Mörgelin M. , Norrby-Teglund A. . ( 2010; ). M1 protein-dependent intracellular trafficking promotes persistence and replication of Streptococcus pyogenes in macrophages. . J Innate Immun 2:, 534–545. [CrossRef] [PubMed]
    [Google Scholar]
  16. Hill P. A. . ( 1998; ). Bone remodelling. . Br J Orthod 25:, 101–107. [CrossRef] [PubMed]
    [Google Scholar]
  17. Ishimi Y. , Miyaura C. , Jin C. H. , Akatsu T. , Abe E. , Nakamura Y. , Yamaguchi A. , Yoshiki S. , Matsuda T. . & other authors ( 1990; ). IL-6 is produced by osteoblasts and induces bone resorption. . J Immunol 145:, 3297–3303.[PubMed]
    [Google Scholar]
  18. Jazayeri J. A. , Carroll G. J. , Vernallis A. B. . ( 2010; ). Interleukin-6 subfamily cytokines and rheumatoid arthritis: role of antagonists. . Int Immunopharmacol 10:, 1–8. [CrossRef] [PubMed]
    [Google Scholar]
  19. Karsenty G. . ( 2012; ). The mutual dependence between bone and gonads. . J Endocrinol 213:, 107–114. [CrossRef] [PubMed]
    [Google Scholar]
  20. Kishimoto T. , Akira S. , Taga T. . ( 1992; ). Interleukin-6 and its receptor: a paradigm for cytokines. . Science 258:, 593–597. [CrossRef] [PubMed]
    [Google Scholar]
  21. Kriete A. , Mayo K. L. . ( 2009; ). Atypical pathways of NF-κB activation and aging. . Exp Gerontol 44:, 250–255. [CrossRef] [PubMed]
    [Google Scholar]
  22. Lew D. P. , Waldvogel F. A. . ( 2004; ). Osteomyelitis. . Lancet 364:, 369–379. [CrossRef] [PubMed]
    [Google Scholar]
  23. Lombardi G. , Di Somma C. , Rubino M. , Faggiano A. , Vuolo L. , Guerra E. , Contaldi P. , Savastano S. , Colao A. . ( 2011; ). The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics. . J Endocrinol Invest 34: (7 Suppl.), 18–22.[PubMed]
    [Google Scholar]
  24. Marriott I. , Hughes F. M. Jr , Bost K. L. . ( 2002; ). Bacterial infection of osteoblasts induces interleukin-1β and interleukin-18 transcription but not protein synthesis. . J Interferon Cytokine Res 22:, 1049–1055. [CrossRef] [PubMed]
    [Google Scholar]
  25. McDevitt D. , Francois P. , Vaudaux P. , Foster T. J. . ( 1994; ). Molecular characterization of the clumping factor (fibrinogen receptor) of Staphylococcus aureus. . Mol Microbiol 11:, 237–248. [CrossRef] [PubMed]
    [Google Scholar]
  26. Montanaro L. , Testoni F. , Poggi A. , Visai L. , Speziale P. , Arciola C. R. . ( 2011; ). Emerging pathogenetic mechanisms of the implant-related osteomyelitis by Staphylococcus aureus . . Int J Artif Organs 34:, 781–788. [CrossRef] [PubMed]
    [Google Scholar]
  27. Ning R. , Zhang X. , Guo X. , Li Q. . ( 2010; ). Attachment of Staphylococcus aureus is required for activation of nuclear factor kappa B in human osteoblasts. . Acta Biochim Biophys Sin (Shanghai) 42:, 883–892. [CrossRef] [PubMed]
    [Google Scholar]
  28. O’Brien L. , Kerrigan S. W. , Kaw G. , Hogan M. , Fitzgerald D. J. , Foster T. , Cox D. . ( 2002; ). Multiple mechanisms for the activation of human platelet aggregation by Staphylococcus aureus: roles for the clumping factors ClfA and ClfB and the serine-aspartate repeat protein SdrE. . Mol Microbiol 44:, 1033–1044. [CrossRef] [PubMed]
    [Google Scholar]
  29. Oviedo-Boyso J. , Cortés-Vieyra R. , Huante-Mendoza A. , Yu H. B. , Valdez-Alarcón J. J. , Bravo-Patiño A. , Cajero-Juárez M. , Finlay B. B. , Baizabal-Aguirre V. M. . ( 2011; ). The phosphoinositide-3-kinase-Akt signaling pathway is important for Staphylococcus aureus internalization by endothelial cells. . Infect Immun 79:, 4569–4577. [CrossRef] [PubMed]
    [Google Scholar]
  30. Panzer U. , Steinmetz O. M. , Turner J.-E. , Meyer-Schwesinger C. , von Ruffer C. , Meyer T. N. , Zahner G. , Gómez-Guerrero C. , Schmid R. M. . & other authors ( 2009; ). Resolution of renal inflammation: a new role for NF-kappaB1 (p50) in inflammatory kidney diseases. . Am J Physiol Renal Physiol 297:, F429–F439. [CrossRef] [PubMed]
    [Google Scholar]
  31. Rao N. , Ziran B. H. , Lipsky B. A. . ( 2011; ). Treating osteomyelitis: antibiotics and surgery. . Plast Reconstr Surg 127: (Suppl. 1), 177S–187S. [CrossRef] [PubMed]
    [Google Scholar]
  32. Scharf S. , Zahlten J. , Szymanski K. , Hippenstiel S. , Suttorp N. , N’Guessan P. D. . ( 2012; ). Streptococcus pneumoniae induces human β-defensin-2 and -3 in human lung epithelium. . Exp Lung Res 38:, 100–110. [CrossRef] [PubMed]
    [Google Scholar]
  33. Sims N. A. , Gooi J. H. . ( 2008; ). Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption. . Semin Cell Dev Biol 19:, 444–451. [CrossRef] [PubMed]
    [Google Scholar]
  34. Sinha B. , François P. P. , Nüsse O. , Foti M. , Hartford O. M. , Vaudaux P. , Foster T. J. , Lew D. P. , Herrmann M. , Krause K. H. . ( 1999; ). Fibronectin-binding protein acts as Staphylococcus aureus invasin via fibronectin bridging to integrin α5β1 . . Cell Microbiol 1:, 101–117. [CrossRef] [PubMed]
    [Google Scholar]
  35. Tucker K. A. , Reilly S. S. , Leslie C. S. , Hudson M. C. . ( 2000; ). Intracellular Staphylococcus aureus induces apoptosis in mouse osteoblasts. . FEMS Microbiol Lett 186:, 151–156. [CrossRef] [PubMed]
    [Google Scholar]
  36. Vander Have K. L. , Karmazyn B. , Verma M. , Caird M. S. , Hensinger R. N. , Farley F. A. , Lubicky J. P. . ( 2009; ). Community-associated methicillin-resistant Staphylococcus aureus in acute musculoskeletal infection in children: a game changer. . J Pediatr Orthop 29:, 927–931. [CrossRef] [PubMed]
    [Google Scholar]
  37. Widaa A. , Claro T. , Foster T. J. , O’Brien F. J. , Kerrigan S. W. . ( 2012; ). Staphylococcus aureus protein A plays a critical role in mediating bone destruction and bone loss in osteomyelitis. . PLoS ONE 7:, e40586. [CrossRef] [PubMed]
    [Google Scholar]
  38. Wright J. A. , Nair S. P. . ( 2010; ). Interaction of staphylococci with bone. . Int J Med Microbiol 300:, 193–204. [CrossRef] [PubMed]
    [Google Scholar]
  39. Yoshii T. , Magara S. , Miyai D. , Nishimura H. , Kuroki E. , Furudoi S. , Komori T. , Ohbayashi C. . ( 2002; ). Local levels of interleukin-1β, -4, -6 and tumor necrosis factor α in an experimental model of murine osteomyelitis due to Staphylococcus aureus . . Cytokine 19:, 59–65. [CrossRef] [PubMed]
    [Google Scholar]
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