Early Subchondral Bone Loss at Arthritis Onset Predicted Late Arthritis Severity in a Rat Arthritis Model

Abstract

Synovitis is usually observed before loss of articular function in rheumatoid arthritis (RA). In addition to the synovium and according to the "Inside-Outside" theory, bone compartment is also involved in RA pathogenesis. Then, we investigated time dependent articular bone loss and prediction of early bone loss to late arthritis severity on the rat adjuvant-induced arthritis (AIA) model. Lewis female rats were longitudinally monitored from arthritis induction (day 0), with early (day 10) and late (day 17) steps. Trabecular and cortical microarchitecture parameters of four ankle bones were assessed by microcomputed tomography. Gene expression was determined at sacrifice. Arthritis occurred at day 10 in AIA rats. At this time, bone erosions were detected on four ankle bones, with cortical porosity increase (+67%) and trabecular alterations including bone volume fraction (BV/TV: -13%), and trabecular thickness decrease. Navicular bone assessment was the most reproducible and sensitive. Furthermore, strong correlations were observed between bone alterations at day 10 and arthritis severity or bone loss at day 17, including predictability of day 10 BV/TV to day 17 articular index (R = 0.76). Finally, gene expression at day 17 confirmed massive osteoclast activation and interestingly provided insights on strong activation of bone formation inhibitor markers at the joint level. In rat AIA, bone loss was already observed at synovitis onset and was predicted late arthritis severity. Our results reinforced the key role of subchondral bone in arthritis pathogenesis, in favour to the "Inside-Outside" theory. Mechanisms of bone loss in rat AIA involved resorption activation and formation inhibition changes. J. Cell. Physiol. 232: 1318-1325, 2017. © 2016 Wiley Periodicals, Inc.

Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model

“…So, a robust animal model with high arthritis rate and synchronicity was required to explore the preclinical phase. As we showed previously, the rat AIA model met these requirements 12 . A previous study using the same model reported increased osteoclast activity at the time of arthritis and later 26 .…”

“…Control rats (CTRL group, n = 35) received only mineral oil. Injection was performed under short and light 2% isoflurane anaesthesia to optimize the full deliverance of the dose and obtain a high rate of arthritis induction 12 . The day of arthritis induction was defined as day 0.…”

“…In vivo follow-up included animal care and appreciation of overall welfare. Body mass, AI, and ankle circumferences were recorded as previously described 12 . Briefly, AI was measured by a blinded observer and summarized clinical inflammation status, mainly erythema; while ankle circumference delivered a quantitative assessment of joint swelling.…”

“…In the female Lewis rat adjuvant-induced arthritis (AIA) model, ankle bone porosity was increased with trabecular bone loss at the day of clinical arthritis onset, occurring mainly at the navicular bone site 12 . Furthermore, these early signs predicted later inflammation and bone loss outcome.…”

Porphyromonas gingivalisexperimentally induces periodontis and an anti-CCP2-associated arthritis in the rat

“…Five rats per group were sacrificed after 1 month and the others at 8 months. Rat in vivo monitoring,10 periodontitis validation, biochemistry assays and determination,11 microcomputed analysis and bone histology methods12 were described in the supplementary methods section. Non-parametric tests were performed with p values under 0.05 considered as statistically significant.…”