eCM (Eur Cell Mater / e Cells & Materials) Not-for-Profit Open Access
Created by Scientists, for Scientists
 ISSN:1473-2262         NLM:100973416 (link)         DOI:10.22203/eCM

2019   Volume No 37 – pages 402-419

Title: The role of bacterial stimuli in inflammation-driven bone formation

Authors: M Croes, MC Kruyt, W Boot, B Pouran, MVJ Braham, SA Pakpahan, H Weinans, HC Vogely, AC Fluit, WJA Dhert, J Alblas, FC Öner

Address: Department of Orthopaedics University Medical Centre Utrecht, Rm G05.228, P.O. Box 85500, Utrecht 3508 GA, the Netherlands.

E-mail: j.alblas at

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.

Key Words: Osteoimmunology, osteomyelitis, stromal/stem cells, osteoblasts, BMPs/TGF-beta, toll-like-receptors.

Publication date: May 16th 2019

Article download: Pages 402-419 (PDF file)


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