engleski

TNF-alpha receptor 1 controls endochondral bone formation in adult mice

TNF-alpha, a major proinflammatory cytokine, exerts its role on bone cells through two receptors (TNFR1 and TNFR2). TNFR1, but not TNFR2, is expressed by osteoblasts and its function in bone formation in vivo is not fully understood. We compared in vivo new bone formation in mice deficient for TNFR1 (TNFR1 -/-) and wild-type mice, using two models of bone formation: intramembranous ossification following tibial marrow ablation and endochondral ossification induced by bone morphogenetic protein (BMP)-2. Intramembranous osteogenesis in TNFR1 -/- mice did not differ from the wild-type mice either in histomorphometric parameters or mRNA expression of bone-related markers and inflammatory cytokines. During endochondral osteogenesis, TNFR1 -/- mice formed more cartilage (at post-implantation day 9), followed by more bone and bone marrow (at day 12). There was no difference in expression of bone-related markers (collagen , osteopontin, bone sialoprotein and osteocalcin), between the TNFR1 -/- and wild-type mice, indicating that signalling through the TNFR1 controls proliferation but not differentiation during postnatal endochondral ossification. mRNA and BMP-2, -4, and -7 were increased during the endochondral differentiation sequence in TNFR1 -/- mice. The expression of RANKL and RANK, as assessed by quantitative RT-PCR, was also significantly increased during endochondral ossification in TNFR1 -/- mice. In conclusion, signalling through the TNFR1 is a negative regulator of new tissue formation during endochondral but not intramembranous osteogenesis in an adult organism. BMPs and RANKL and its receptor RANK seem to be involved in the change of local environment in the absence of TNFR1 signalling.

bone; mice; immune system

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