The role of bacterial stimuli in inflammation-driven bone formation

M. Croes, M. C. Kruyt, W. Boot, B. Pouran, M. V. Braham, S.A. Pakpahan, H. Weinans, H.C. Vogely, A.C. Fluit, W.J. Dhert, J. Alblas, F.C. Öner

Research output: Contribution to journalArticleScientificpeer-review

10 Citations (Scopus)
32 Downloads (Pure)

Abstract

Immune cells and their soluble factors regulate skeletal cells during normal bone regeneration and pathological bone formation. Bacterial infections can trigger immune responses that activate pro-osteogenic pathways, but these are usually overshadowed by osteolysis and concerns of systemic inflammation. The aim of this study was to determine whether the transient local inflammatory reaction to non-viable bacterial immune agonists could lead to favourable new bone formation. In a series of rabbit studies, as proof-of-concept, how tibial intramedullary injection of viable or killed bacterial species affected bone remodelling and new bone formation was determined. Application of killed bacteria led to considerable new bone formation after 4 weeks, without the prolonged systemic inflammation and exaggerated bone lysis seen with active infection. The osteo-immunomodulatory effects of various species of killed bacteria and the dose response relationship were subsequently screened in ectopically-implanted ceramic scaffolds. Histomorphometry after 8 weeks showed that a relatively low dose of killed bacteria enhanced ectopic bone induction. Moreover, lipoteichoic acid - the bacterial cell-wall derived toll-like-receptor (TLR)-2 activator - was identified as an osteo-stimulatory factor. Collectively, the data indicated that bacterial stimuli could be harnessed to stimulate osteogenesis, which occurs through a synergy with osteoinductive signals. This finding holds promise for the use of non-viable bacteria, bacterial antigens, or their simplified analogues as immuno-modulatory bone regenerating tools in bone biomaterials.

Original languageEnglish
Pages (from-to)402-419
JournalEuropean Cells & Materials
Volume37
DOIs
Publication statusPublished - 2019

Keywords

  • osteoimmunology
  • osteomyelitis
  • stromal/stem cells
  • osteoblasts
  • BMPs/TGF-beta
  • toll-likereceptors

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