Toll-like receptor induced inflammation causes local bone formation

• It is well established that inflammatory processes in the vicinity of bone often induce osteoclast formation and bone resorption. Effects on bone formation by inflammatory processes are much less studied and available information is partly contradictory. In the present study, we have assessed the effect on bone formation by locally induced inflammation. LPS from Porphyromonas gingivalis and Pam2, used as Toll-like receptor (TLR) 2 agonists, and flagellin from Salmonella typhimurium, used as TLR5 agonist, were injected subcutaneously on the top of mouse skull bones. After 1-5 days, the calvarial bones were dissected and processed either for histological or gene expression analyses. Femur was dissected for analysis with microCT and histology. At day 5, all three agonists induced bone formation on periosteal and endosteal sites, as well as in the bone marrow compartment of the calvaria. This response was seen both in close vicinity to, but also apart from, osteoclasts and bone resorption cavities. In areas close to new bone formation, abundance of proliferating cells was observed as assessed by Ki67 labelling. Gene expression analyses showed that Pam2 treatment resulted in increased mRNA expression at day 5 of genes encoding bone matrix proteins, alkaline phosphatase and of the osteoblastic transcription factors Runx2 and osterix. Robust Runx2 protein was observed in osteoblasts in areas with new bone formation. Pam2 treatment also increased the mRNA expression of cytokines in the IL-6 family, as well as of their cognate receptors and common signaling transduction subunit gp130. At day 5, the mRNA expression of Bmp2, Bmp4, Tgfb1, Lrp5, Lrp6 and Wnt7b was increased, whereas Sost was decreased. In the femur, excessive osteoclast formation and trabecular bone loss was found at day 5, but new bone formation was not observed. In conclusion, these data show that inflammatory processes not only induce osteoclastogenesis but also have the capacity to activate osteoblasts and stimulate new bone formation distinct from bone remodeling sites. Stimulation of inflammation- induced new bone formation may be due to enhanced gp130 signaling. Osteoblast activation in the inflammatory processes may also involve the BMP and WNT signaling systems.

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MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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