Abstract
BackgroundThe anterior cruciate ligament (ACL) has a key role as a dynamic stabilizer of the knee joints, and ACL dysfunction caused by traumatic or degenerative rupture accelerates osteoarthritis progression. Thus, it is important to prevent the degenerative rupture of the ACL. 4-Methylumbelliferone (4-MU), a pre-approved drug, exerts anti-inflammatory effects in osteoarthritis chondrocytes. It was originally used as an inhibitor of hyaluronan synthesis in chondrocytes.MethodsIn this study, we investigated whether 4-MU affects the expression of catabolic factors, such as matrix metalloproteinase (MMP)-1, MMP-3, and interleukin (IL)-6, in ACL-derived cells and ACL explant cultures using immunohistochemistry, real-time RT-qPCR, and capillary western immunoassay. Furthermore, the hyaluronan concentration was evaluated using a colorimetric assay. Statistical analyses were conducted using analysis of variance for multi-group comparisons, followed by Tukey or Tukey-Kramer post hoc test.ResultsOur results revealed, for the first time, that 4-MU suppressed the IL-β-induced upregulation of pro-catabolic factors, such as MMP-1, MMP-3, and IL-6, in ACL-derived cells. This suppressive effect was also observed in the cultured ligament tissues in ex vivo experiments. 4-MU also reversed an enhanced dependence on glycolysis in IL-1β-activated ACL-derived cells. Furthermore, we found that the suppressive effects of 4-MU were exerted directly and not through the inhibition of hyaluronan synthesis.ConclusionsWe conclude that 4-MU could be an effective and useful treatment for knee osteoarthritis, owing to its anti-inflammatory effect on, not only chondrocytes but also on ligament cells.
Highlights
The anterior cruciate ligament (ACL) has a key role as a dynamic stabilizer of the knee joints, and ACL dysfunction caused by traumatic or degenerative rupture accelerates osteoarthritis progression
The levels of mRNA expression of matrix metalloproteinase (MMP)-1, MMP-3, and IL-6 in human ACL-derived cells trends increase after a 12-h treatment with IL-1β (0.001–10 ng/mL) (Fig. 1A)
Here, we demonstrated for the first time that the IL-1βinduced expression of MMP-1, MMP-3, and IL-6 was suppressed by 4-MU treatment in a dose-dependent manner in human ACL-derived cells
Summary
The anterior cruciate ligament (ACL) has a key role as a dynamic stabilizer of the knee joints, and ACL dysfunction caused by traumatic or degenerative rupture accelerates osteoarthritis progression. Previous studies have reported that various OA-related cytokines and enzymes induce inflammation and degeneration of all joint components, including the cartilage, synovia, menisci, and ligaments [2]. Among these intra-articular tissues, the anterior cruciate ligament (ACL) has a key role as a dynamic stabilizer of the knee joint, and previous studies have shown that ACL dysfunction caused by traumatic or degenerative rupture accelerates OA progression [1]. Severe degenerative changes following ACL rupture in the knee joint might enhance OA development synergistically [6]
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