Abstract
Osteoarthritis (OA) is an age-related disease marked by synovial inflammation and cartilage destruction arising from synovitis, joint swelling and pain. OA therapy that targets the synovium is a promising strategy for mitigating the symptoms and disease progression. Altered activity of the transforming growth factor-β1 isoform (TGF-β1) during aging underlies OA progression. Notably, aberrant forkhead box class O 3 (FOXO3) activity is implicated in the pathogenesis of various age-related diseases, including OA. This study explored the interaction and cross-talk of TGF-β1 and FOXO3 in human osteoarthritis synovial fibroblasts (OASFs). TGF-β1 stimulated FOXO3 synthesis in OASFs, which was mitigated by blocking adenosine monophosphate-activated protein kinase (AMPK) and p38 activity. TGF-β1 also inhibited the expression of miR-92a, which suppresses FOXO3 transcription. The suppression of miR-92a was effectively reversed with the blockade of the AMPK and p38 pathways. Our study showed that TGF-β1 promotes anti-inflammatory FOXO3 expression by stimulating the phosphorylation of AMPK and p38 and suppressing the downstream expression of miR-92a. These results may help to clarify OA pathogenesis and lead to better targeted treatment.
Highlights
Osteoarthritis (OA) is marked by synovial inflammation, cartilage destruction, joint swelling and pain
transforming growth factor-β1 isoform (TGF-β1) stimulates the expression of forkhead box class O 3 (FOXO3) in human osteoarthritis synovial fibroblasts (OASFs)
Stimulation of OASFs with TGF-β1 diminished the mRNA and protein expression of inflammatory mediators, including TNFα, IL-1β, VEGF and CCL2 (Fig. 1B-D). Both TGF-β1 and FOXO3 have been shown to be involved in the pathogenesis of OA, as well as the aging process [10, 19]
Summary
Osteoarthritis (OA) is marked by synovial inflammation, cartilage destruction, joint swelling and pain. Age-associated inflammation is a key contributor to the pathogenesis of OA [1, 2], as a result of continuous mechanical wear and tear and/or age-related modifications of the cartilage matrix. The synthesis of pro-inflammatory and hydrolytic mediators by the inflamed synovium can induce cartilage erosion, which amplifies synovial inflammation, creating a vicious cycle. OA synovial cells maintain arthritic pathologies by synthesizing the inflammatory mediators and matrix degradation enzymes [5,6,7]. Research has begun to focus on synovium-targeted therapy in the attempt to halt the progression and lessen the impact of OA symptoms [8, 9]
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