Background/Purpose:  Periarticular bone loss in rheumatoid arthritis is considered to be mainly related to synovial inflammation, leading to uncoupling between decreased bone formation and increased bone resorption. However, it has been recently demonstrated a paradoxical exacerbation of joint damage when blocking sclerostin in various arthritis models. Phase specific changes in Wnt pathway activity over the course of the disease could participate in the underlying mechanisms of these results. Thus, we proposed to determine kinetic expressions of Wnt inhibitors in a classic rodent model of arthritis, the rat adjuvant induced arthritis (AIA).

Methods:  Arthritis was induced (AIA, n=35) or not (CTRL, n=35) at baseline. Inflammation and loss of articular function were monitored. Periarticular bone loss and joint damage were evaluated before, during and after arthritis onset in a 7 time-point follow-up, using micro-computed tomography (µ-CT) and histomorphometry. Gene expressions were assessed by quantitative RT-PCRs at each time point.

Results:  AIA onset occurred at day 12 post-induction (p<0.001). Surprisingly, histomorphometry and µ-CT showed bone alterations as early as day 8. Indeed, cortical porosity increased and trabecular network was significantly impaired (p<0.01). Moreover, these early bone alterations before arthritis onset predicted arthritis severity outcome. As expected, gene expression confirmed an early upregulation of bone resorption markers like RANKL from day 8 to day 24 (p<0.01). More interestingly, expression of bone formation inhibitors followed a specific pattern with SOST upregulation only before arthritis onset (p<0.01) and return to normal expression afterwards. However, frizzled related protein 1 (SFRP1) expression only increased after arthritis onset (p<0.01). Furthermore, dickkopf related protein 1 (DKK1) expression increased before and after arthritis onset with a low expression during arthritis onset. Figure: gene expression pattern of SOST, DKK1, and SFRP1.

Conclusion:  Bone alterations before arthritis onset supports the hypothesis of an early involvement of bone compartment in arthritis. The specific pattern of sclerostin expression suggested that sclerostin might play dual effects depending on arthritis phases. In addition, SFRP1 later increased expression could play a strong role in bone formation alteration related to arthritis. Since DKK-1 was highly expressed before and after arthritis onset, its blockade was already described to be efficient in mice arthritic model. We infer from our results that better deciphering Wnt pathway changes during arthritis is required before using biologics targeting this pathway for preventing periarticular bone loss.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-expression-of-wnt-inhibitors-before-and-after-joint-inflammation-onset-in-rat-arthritis-could-partly-explain-paradoxical-effect-of-sclerostin-inhibition/