Abstract
To investigate the role of glycogen metabolism in regulating rheumatoid fibroblast-like synoviocyte (FLS)-mediated synovial inflammation and its underlying mechanism. FLSs were separated from synovial tissues (STs) obtained from rheumatoid arthritis (RA) patients. Glycogen content was determined by periodic acid Schiff staining. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression of cytokines and matrix metalloproteinases (MMPs) was evaluated by quantitative real-time PCR. FLS proliferation was detected by EdU incorporation. Migration and invasion were measured by Boyden chamber assay. Glycogen levels and glycogen synthase 1 (GYS1) expression were significantly increased in the ST and FLSs of RA patients. TNF-α or hypoxia induced GYS1 expression and glycogen synthesis in RA FLSs. GYS1 knockdown by shRNA decreased the expression of IL-1β, IL-6, CCL-2, MMP-1, and MMP-9 and proliferation and migration by increasing AMP-activated protein kinase (AMPK) activity in RA FLS. AMPK inhibitor or knockdown AMPK could reverse the inhibitory effect of GYS1 knockdown on the inflammatory response in RA FLSs; however, an AMPK agonist blocked RA FLS activity. We further determined that hypoxia-inducible factor-1α mediates TNF-α- or hypoxia-induced GYS1 expression and glycogen levels. Local joint depletion of GYS1 or intraperitoneal administration with an AMPK agonist ameliorated the severity of arthritis in rats with collagen-induced arthritis. Our data demonstrate that GYS1-mediated glycogen accumulation contributes to FLS-mediated synovial inflammation in RA by blocking AMPK activation. In our knowledge, this is a first study linking glycogen metabolism to chronic inflammation. Inhibition of GYS1 might be a novel therapeutic strategy for chronic inflammatory arthritis, including RA.
Highlights
Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by the progressive destruction of cartilage and bone
We demonstrated that glycogen synthesis and glycogen synthase 1 (GYS1) expression are significantly increased in the synovial tissue (ST) of RA patients and rats with Collagen-Induced Arthritis (CIA) and that GYS1 knockdown by shRNA inhibits the expression of pro-inflammatory cytokines and Matrix Metalloproteinases (MMPs) and the proliferation, migration, and invasion of cells by increasing AMPK activity
We determined that GYS1-mediated glycogen accumulation in synovial inflammation is regulated by the suppression of excessive AMPK activity in RA, providing novel evidence that abnormal glycogen synthesis contributes to chronic inflammation
Summary
Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by the progressive destruction of cartilage and bone. Stable activated FLSs in RA exhibit tumor-like characteristics, such as anchorage-independent growth and resistance to apoptosis [3, 4], and play a crucial role in the development of pannus by migration and invasion toward cartilage and bone [5, 6]. Targeting the reprogramming of glucose metabolism has been considered as an attractive new approach to develop new therapeutics in cancer treatment [8, 9]. Some studies have suggested that aberrant glycolytic activity is associated with synovial tissue (ST) destruction and the auto immune response in RA [8, 9], the role of glucose metabolism in the pathogenesis of RA has not received adequate attention
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