Clusterin, a potential pathophysiological actor in rheumatoid arthritis

Aim

To ameliorate the understanding of the mechanisms involved in rheumatoid arthritis (RA) and to identify new therapeutic targets and develop novel diagnosis tools. The microarray technology allowed us to identify a set of gene specifically expressed in the synovial tissue of RA patients in comparison with osteoarthritis (OA). Among them, we focused on clusterin since it has multiple functions related to the pathophysiological processes suspected to be involved in RA.

Results

Using real-time quantitative PCR on a larger set of samples than on the microarray study, we demonstrated the highly significant (P < 0.0001) underexpression of clusterin in RA versus OA and versus synovial tissues of healthy individuals. The fold differential expression between OA and RA was 9.8 and between healthy tissue and RA was close to 5.2. Northern blot analysis further confirmed this differential expression and did not demonstrate an alternative splicing form of mRNA between RA and OA. Immunohistochemistry analyses of synovial tissues demonstrated that clusterin protein was mainly localised in synovial cells. The differential expression between OA and RA persisted in third-passage synovial cells. Western blot extended this differential expression at the protein level and pointed towards specific impairment of protein isoforms in RA tissues compared with OA tissues. The differential expression concerned both the intracellular and nuclear isoforms of the protein as evidenced by real-time quantitative PCR and western blot analysis.

Conclusions

Due to the numerous functions associated with clusterin, the strong underexpression of clusterin mRNA in RA synovial tissue, which is associated with the specific impairment of the intracellular forms of the protein, could have tremendous effects on several pathophysiological processes taking place in RA.