0105: Inflammatory Cytokines, Matrix Metalloproteinases and Bone Markers Expressions Are Modulated in the Joints in the Chronic Murine Model of Imiquimod-Induced Psoriasis

Background/Purpose: Psoriatic disease is a systemic inflammatory condition which encompasses both cutaneous psoriasis (PsO), psoriatic arthritis (PsA) and multiple comorbidities. The chronic Imiquimod (IMQ) induced psoriasiform dermatitis mouse model is a classical model to study psoriasis and has been used in analysing psoriasis associated liver fibrosis. However less is known about joint inflammation and cytokines modification after IMQ psoriasis induction. The objectives of this study were to analyse the expression of cytokines, metalloproteinases and bone markers inside the mice’s joints to evaluate the potential of long-term application of IMQ as a new PsA mouse model as well as the involvment of Oncostatin M (OSM).

Methods: Wild type (WT) and OSM-KO male C57BL/6 mice were studied. For the induction of PsO-like inflammation, mice were shaved and depilated on their back before a daily topical application of 62.5 mg of Aldara cream (5% IMQ; Meda) for six consecutive days every other week during 5 (W5) to 9 weeks (W9). Control mice were treated with a similar dose of Vaseline. Mice were euthanized after 5 weeks or 9 weeks of treatment. Knee joints were dissected, collected, rapidly frozen in liquid nitrogen. Total RNA was extracted, reverse transcribed, and transcripts were quantified using the LightCycler-FastStart DNA Master Plus SYBR Green I kit on LightCycler 480 instrument. Samples were normalized to the independent control housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and reported according to the ∆∆CT method as RNA fold increase over untreated samples. Comparison were made using Mann Whitney test. p-values < 0.05 were considered significant.

Results: Chronic application of IMQ on the mice skin induced a pro-inflammatory state within the joints as shown by the increased expression of TNF alpha at W5 and W9 in both WT and OSM-KO mice and decreased expression of the anti-inflammatory cytokine PEDF. IL-1 family cytokines seem to be implicated in the initiation of the inflammatory response as suggested by IL1a increase at W5 in the IMQ treated WT mice and the decreased expression at W9 of IL-18. IL10 expression was increased at both W5 and W9 indicating an attempt to regulate joint’s inflammation. While at W5 no difference was observed for MMP3, MMP9, and MMP13, a lower expression was found in IMQ treated mice for MMP3 and MMP13 at W9 while no difference were observed for MMP9. Concerning bone turnover, no modification of Sclerostin was found in both groups at W5 and W9 while there was a DKK1 expression decrease only in the WT group at both W5 and W9. M-CSF, an osteoclast differentiation driver, was decreased only at W9 in both groups and at W5 in the WT group only. These results confirm the role of OSM as a modulator of bone biology upon inflammatory conditions. No difference was found at both W5 and W9 for IL1B, VEGFa, MMP9, SOST, TLR7, TRPV1, IL1RA in both groups.

Conclusion: In the long term IMQ induced psoriasis mouse model intra-articular inflammation is observed and modifications of bone cell markers as well as metalloproteinases expression are modulated in a time dependant manner. Those results pave the way to a more detailed analysis of this model which seems a promising new PsA model as well as a PsO to PsA mechanistic model.