engleski

Role of TNF receptor 1-mediated signaling in BMP-induced osteogenesis in vivo

Tumor necrosis factor-a (TNF-a) is among the most potent bone-acting cytokines produced in inflammation. Its effects on bone cells are predominantly mediated through the p55 receptor (TNFR1). To test the role of TNF-a in osteogenesis, we used a well-defined model of ectopic induction of new bone in vivo by recombinant human bone morphogenetic protein-2 (rhBMP-2) in mice with a gene knockout for TNFR1 (TNFR1-/- mice). rhBMP-2 was implanted in syngeneic blood clot into a subcutaneous patch in the pectoral region. New bone formation was assessed by histomorphometry, Northern blot analysis of bone-specific proteins, and RT-PCR for inflammatory cytokines and BMPs*. The mass of the newly induced ossicles was greater in TNFR1-/- mice compared with wild type controls (C57BL/6 strain), especially at the time of intensive cartilage proliferation 9 days after rhBMP-2 implantation (2.49ą0.24 vs. 1.29ą0.57 g, respectively ; p<0.05). Histomorphometry of serial sections of newly induced ossicles demonstrated greater volume of newly induced mesenchyme in TNFR1-/- mice 6 days after rhBMP-2 implantation, cartilage at 9 post-implantation days, and bone and bone marrow on 12 postimplantation days. Osteocalcin mRNA was increased at later stages of ossicle development (9 and 12 post-implantation days). IL-a mRNA was greatly increased at the same time points. BMP-2 and -4 mRNA was increased at earlier differentiation stages, whereas the expression of BMP-7 was similar to that of IL-1a. Our results suggest that signaling through the TNFR1 receptor is important for the normal cellular sequence of osteoinduction, and especially for the development of cytokine pattern in the newly developing bone.

cytokines; bone induction; bone morphogenetic proteins

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