ECTS Abstracts (2015) 1 P306

Analysis of Osteoimmune Interactions in Transgenic Mice Overexpressing Human RANKL

Maria Papadaki1,2, Vagelis Rinotas1,2, George Kollias2 & Eleni Douni1,2

1Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855, Athens, Greece; 2B.S.R.C. “Alexander Fleming”, Fleming 34, 16672, Athens, Greece.

Receptor activator of nuclear factor-κB ligand (RANKL) is a central regulator of bone remodelling by mediating osteoclast-induced bone resorption. We have recently generated transgenic mice (TghuRANKL) carrying the human RANKL (huRANKL) genomic region and achieved a physiologically relevant pattern of RANKL overexpression. TghuRANKL mice of both sexes developed early-onset bone loss and the levels of huRANKL expression were correlated with bone resorption and disease severity. Low copy Tg5516 mice expressing huRANKL at low levels displayed a mild osteoporotic phenotype as shown by trabecular bone loss and reduced biomechanical properties. Notably, overexpression of huRANKL, in the high copy Tg5519 line, resulted in severe early-onset osteoporosis featured by lack of trabecular bone, destruction of the growth plate, increased osteoclastogenesis, increased cortical bone remodelling and severe cortical bone porosity accompanied by decreased bone strength. Anti-RANKL therapies fully corrected the osteoporotic phenotypes of TghuRANKL mice, promoting their significance for the preclinical evaluation of novel drugs targeting RANKL. Apart from the skeletal system, RANKL is also expressed in lymphoid tissues. Analysis of the Tg5519 immune profile demonstrated severe leukopenia in the bone marrow (BM) followed by a parallel increase in BM adiposity. Moreover, an increase of the percentage of B lymphocytes was identified in the spleen of Tg5519 mice, similarly to other osteoporotic mouse models. The involvement of lymphocytes in the osteoporotic phenotype is currently under investigation using reciprocal BM transplantation experiments. In addition, we investigated the role of RANKL in the progression of inflammatory arthritis, by crossing Tg5519 mice with the Tg197 TNF-driven mouse model of arthritis. Our results showed that the simultaneous overexpression of RANKL and TNF resulted in an aggressive inflammatory phenotype characterized by accelerated pannus formation and bone erosion. These results reveal an interaction between skeletal and immune systems during osteoporosis and imply a modulatory role of RANKL in inflammatory arthritis.

Disclosure: The authors declared no competing interests. This work was supported by the Initial Training Network Osteoimmune (grant 289150) funded by the EC 7th Framework Program.

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