Osteoclasts on bone and dentin in vitro: Mechanism of degradation and comparison of resorption behaviour

Abstract

Glucorticoids (GCs) belong since their discovery to the standard therapy of rheumatoid arthritis (RA), a severe auto-inflammatory bone disease. One major side effect of GCs affects the bone itself leading to GC induced osteoporosis (GIO), the most secondary osteoporosis. GCs act via a receptor (GR) that can alter gene expression by binding as a dimer to GC responsible elements in the promoter region of target genes or by interacting with and thus interfering with other transcription factors as a monomer. We determined the contribution of molecular mechanisms and cell types critically involved in antiinflammatory effects of GCs in RA and on bone using conditional and function selective GR knockout mice. We showed that dimerization of the GR in IL-17 producing T cells is indispensable for the anti-inflammatory effect in the mouse model antigen-induced arthritis. Now we demonstrate that, surprisingly, in the Kbx/N induced arthritis model the GR dimer in mesenchymal cells is critical for anti-inflammatory effects of GCs. Thus, for immunosuppression of arthritis the GR is required in distinct cell types, which are of hematopoietic and mesenchymal origin. In a model of GIO we showed that unexpectedly interaction of the GR monomer with AP-1, but not NF-kB in osteoblasts is decisive for bone loss. Our findings define new criteria for SEGRM that act as an anti-inflammatory and protect the bone. Indeed we identified one lead-compound that still suppresses NF-kB dependent gene expression but does not affect osteoblast differentiation and activity. Furthermorewe identifiednovel GR target genes by functional genomics anddeveloped a screening platform for novel GR agonist-derivatives not affecting osteoblast function. Taken together, our approach gives new insights into GC action on arthritis and bone that can be translated into new concepts for anti-inflammatory therapies preventing GIO. doi:10.1016/j.bone.2012.08.022 O22 Osteoclasts on bone and dentin in vitro: Mechanism of degradation and comparison of resorption behaviour T. Wurger, P. Roschger, E. Zwettler, P. Fratzl, M.J. Rogers, K. Klaushofer, M. Rumpler Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKKand AUVATraumaCenter, 1stMed. Dept., HanuschHospital, Vienna, Austria Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam, Germany The Garvan Institute of Medical Research, Darlinghurst, New SouthWales,