Background and objectives Rheumatoid arthritis (RA) features include synovial inflammation and periarticular bone loss. However, relationships between bone and synovia are not fully understood. We investigated early bone changes before inflammation onset in rat adjuvant-induced arthritis (AIA) and their predictability to later arthritis outcome. Bone loss is mainly due to resorption increase, already largely investigated. However, formation inhibition may be also involved and is poorly explored. Accordingly, we investigated gene expression regarding bone formation, resorption, and matrix degradation.
Materials and methods Arthritis was induced (AIA, n = 35) or not (CTRL, n = 35) in female Lewis rats, and sacrificed at 7 stages. Ankle inflammation was recorded by articular index (AI), loss of function index (LFI), ankle perimeter, and in histological slides. Ankle bones microarchitecture was investigated with micro-computed tomography (µ-CT) and histomorphometry. Gene expression was assessed by quantitative RT-PCRs, and results were normalised to glyceraldehyde-3-phosphate deshydrogenase (GAPDH) expression. Non-parametric statistics were performed. P-values under 0.05 were considered statistically significant.
Results As expected, inflammation parameters differed between CTRL and AIA rats from day 13 (AI, LFI, ankle perimeter, p < 0.001, and weight, p < 0.01), while ankle erosions where detected in µ-CT and histology in AIA rats from day 8. Early microarchitecture defects in ankles were quantifiable, and bone microarchitecture alterations at day 10 correlated with arthritis severity at day 17. Gene expression study revealed an upregulation of bone formation inhibitors such as dickkopf-related protein 1 (DKK1, p < 0.05), secreted frizzled-related protein-1 (SFRP1, p < 0.001), additionally to usual increase of bone resorption and degradation (RANK and RANKL upregulation, p < 0.001 for both, osteoprotegerin downregulation, p < 0.001), and bone matrix degradation (upregulation of matrix metalloproteinase (MMP)-2, p < 0.05, MMP-9, p < 0.001, and acid phosphatase, p < 0.001).
Conclusions Bone alterations might develop in parallel to synovial inflammation, giving new insights for bone compartment role in early RA joint and bone destruction. This early bone loss was predictive to arthritis outcome in the AIA model, and correlated with a lower but existing systemic bone loss. Finally, we observed that deregulation from both formation and resorption take part in this pattern.
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