Use of Mesenchymal Stem Cell Therapy to Target Metalloproteinase Overactivity in Osteoarthritis of the Knee
Introduction. Osteoarthritis (OA) of the knee is a painful, stiffness of the knee joint due to a complex degenerative disease.1 Estimates show that 30.8 million Americans and 40 million Europeans currently suffer from this disease.2 And with an increased age there is an increased prevalence, which is concerning considering the advancing age of our world’s population.1 OA of the knee is diagnosed using x-ray, MRI, arthroscopy and/or fulfilling 6 criteria: age greater than 50, morning stiffness, crepitus on active motion, bony tenderness, bony enlargement, and no detectable warmth. 1 The mechanism of OA of the knee involves an imbalance of many intracellular proteins and enzymes, including metalloproteinases, particularly a distintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 and 5, and tissue inhibitors of metalloproteinases (TIMPS). 3,4 Mesenchymal stem cells (MSCs) have been researched as a potential means of therapy for restoring this imbalance. Current research has shown that MSC exosomes may be directly regulating the beta catenin pathway to achieve this therapy. Methods. Synovial tissue samples were retrieved from patients with and without OA undergoing knee arthroplasty and plated with inflammatory cytokines (IL-1B, Fn-Fs) and inhibitors of the beta-catenin pathway (DKK-1). 4 Additionally, the OA knee model (induced by transecting the medial collateral ligament, the medial meniscus, and the anterior cruciate ligament) was used in rat groups. 5 Controls received saline injections at the same time as the experimental group received cultured MSCs. 5 Tissue samples from human donors were assessed with quantitative PCR, ELISA, and western blot. 4 The researchers using the rat model assessed the knee tissue of the sacrificed rats 8 weeks post-surgery using qPCR, microcomputed tomography and immunohistochemistry. 5 Results. By knocking out the DKK-1 gene in tissue samples of patients with OA, researchers were able to reduce the expressed levels of ADAMTS-4 and ADAMTS-5, thus reducing the level of protein degradation in the joint. 4 Additionally, MSCs used in therapy reduced expression of levels of mixed metalloproteinase-13 and increased expression of TIMP-1, bringing about restored balance within rats induced with OA of the knee. 5 Conclusions. Studies show that a potential mechanism of action in the use of MSCs therapeutically for OA of the knee may involve blocking of the beta-catenin signaling pathway. 4 With reduced levels of metalloproteinases and an overall restored balance within the knee joint, MSC therapy may have the distinct advantage of preventing OA of the knee even prior to clinical symptoms.
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