Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficiency of two major cytokines, namely interleukin (IL)-1 and IL-6, in this study double deficient mice for IL-1αβ and IL-6 were investigated in different tumour necrosis factor (TNF)-driven inflammatory bone disorders, namely peripheral arthritis and sacroiliitis, as well as systemic bone loss. Disease course, histopathological features of arthritis, and micro-CT (µCT) bone analysis of local and systemic bone loss were assessed in 15-week-old Aims
Methods
MicroRNA´s are regulatory sequences which influence the posttranscriptional synthesis of about 70% of protein encoding genes. In different studies, MicroRNA-146a (miR-146a) was associated with inflammatory and autoimmunological processes. In vitro it was shown, that miR-146a influences the bone metabolism by regulating differentiation of mesenchymal stem cells. The miR-146a deficient mouse starts to develop lymphoproliferative and myeloproliferative disease by 6–8 months of age. In this study, we investigate the influence of miR-146a deficiency on bone structure and stability dependent on age and gender. Male and female mice of wild type (WT) and miR-146a deficient (KO) animals at the age of 2–3 and 5–7 month were analyzed Femur, Tibia and lumbar vertebra (LWK4) were dissected and used für structural analyses by microcomputer tomography (µCT). Parameters like bone volume/tissue volume, trabecular bone volume, trabecular thickness, number and separation as well as cortical thickness were determined. Biomechanical stability as Structural analyses of the bone structure in the long bones (femur, tibia) revealed a significant higher bone volume/tissue volume (BV/TV) and trabecular bone mass in the elder (5–7 month) miR-146a deficient female mice compared to the male group or wild type animals of either age. In the diaphysis of the femur a BV/TV of 21% was determined for the elder miR-146a deficient females compared to 9% BV/TV in the age matching WT group. These changes were due to an increase in trabecular thickness and trabecular number in this area. In contrast to that, the cortical thickness of all bones analyzed was lowered in the miR-146a deficient animals (male and female) compared to wild type. Biomechanical stability of long bones as well as the vertebra body of the older, female KO group was significantly lower compared to wild type bones. Femurs showed a maximal torque of 20Nmm compared to 34Nmm in the wild type group. The vertebra of the KO mice showed a maximal force at failure of 22N compared to 40N in the wild type group. Male groups and younger females revealed values comparable to wild type animals.Material and Methods
Results
