Background/Purpose:   Fibroblast-like synovial cells (FLS) play important roles in the disease progression of RA. FLS produce cytokines and chemokines that contribute to chronic inflammation of RA-affected joints. They also secrete matrix metalloproteinases (MMPs) that cause degradation of joint tissues, including bone and cartilages, which leads to severe structural destruction of inflamed joints. We previously reported that the production of IL-6, a cytokine that contributes to the progression of RA, by FLS is reduced by adipogenesis induction. Therefore, we predict that induction of FLS adipogenesis could be a new therapeutic strategy to treat RA. Our objective in this study was to examine whether MMPs production in FLS could be altered by adipogenesis induction.  

Methods:   FLS were isolated from the synovial tissues by enzymatic digestion. MSC were purchased from Lonza (Walkersville, USA). Adipogenesis of FLS was carried out by using the MSC adipogenic differentiation medium BulletKit (Lonza), according to the manufacturer’s instructions. The mRNA expression levels of MMPs and tissue inhibitors of metalloproteinases (TIMPs) were evaluated by DNA array (SurePrint G3 Human GE 8×60K Microarray, Agilent Technologies) by using two-colour detection mode. Production of MMP and TIMP proteins in FLS culture supernatant was evaluated by Human MMP Antibody Array (RayBiotech, Inc., Norcross, USA) and confirmed by ELISA (MMP1, MMP2, and MMP3 purchased from Abcam).

Results:   After adipogenesis induction, transcripts unique to adipocytes (e.g., lipoprotein lipase 4, fatty acid-binding protein 5, fatty acid-binding protein 4, aquaporin 7, perilipin 2, adiponectin, and peroxisome proliferator-activated receptor γ) were clearly induced in FLS, which confirms that adipogenesis was properly induced. Expressions of MMP-1, -2, and -11 transcripts were decreased in FLS following adipogenesis. Conversely, expression of MMP-3 and -25 transcripts was increased by FLS adipogenesis. Consistent with these results, antibody array studies demonstrated that MMP-1 protein production was reduced in FLS culture medium following adipogenesis, whereas MMP-3 protein production increased. Supernatant concentrations of MMP-1 and -2 from FLS obtained from 4 different RA patients were reduced after adipogenesis. The mRNA and protein expression of TIMP-4, a MMP-2 inhibitor, were induced by FLS adipogenesis. 

Conclusion:  Our data demonstrate that MMP-1 and -2 production was inhibited in FLS by adipogenesis induction. If the FLS in pannus were to differentiate into adipocytes with reduced IL-6 and MMPs, the adipocytes would be a more physiological component that would produce fewer pathogenic molecules in the joint. Specifically, the strategy of inducing adipogenesis in FLS may restore both the levels of the harmless cytokine and protease production as well as fat-rich tissue deposition in the affected joint as seen in a normal joint. Further studies are required to include “adipogenesis-induction therapy” in the treatment of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/changes-in-mmp-in-fibroblast-like-synoviocytes-following-adipogenesis/