## 4 Discussion
An improvement in muscle function was associated with significant increases in isokinetic and isometric dynamometry variables, particularly with isokinetic 60\({}^{\circ}\cdot\)s\({}^{-1}\) and 180\({}^{\circ}\cdot\)s\({}^{-1}\) knee flexion exercises. Muscle rehabilitation programs in patients with OA are especially designed to improve muscle function, which can be translated into improved functional performance [57]. However,important and sustained improvements in muscle strength are the benefits achieved with exercise interventions in people with knee OA [58]. Independently of the high content of minerals and vitamins, as well as the antioxidant activity of _Cucumis sativus_, the mechanisms by which cucumber supplementation showed a beneficial effect on muscle function are still unknown and merit further research. This product contains 5% citrulline. citrulline is a potent endogenous precursor of arginine [36], the role of which is involved in the positive regulation of the bioavailability of arginine. Nitric oxide (NO) is a free radical synthesized by arginine by a family of NO synthase (NOS) enzymes. NO synthesis is regulated by the activation of NOS isoforms (inducible NOS (iNOS), endothelial NOS (eNOS) and neuronal NOS (nNOS)). NO generated by iNOS is a potent pro-inflammatory mediator, whereas NO generated by eNOS is involved in the control of cardiovascular homeostasis [37]. Increased NO by stimulation of the synthesis of iNOS by chondrocytes is involved in the pathophysiology of OA. Immunofluorescentes studies of iNOS expression in different cell populations in synovial membrane biopsies of patients with knee OA showed that, during early OA, iNOS is mostly located in macrophages, whereas, in advanced OA, iNOS is also expressed in leukocytes [38]. An increase in citrulline/arginine would be able to inhibit the inflammatory-related reactions produced by iNOS, also producing an increase in the amount of eNOS with vasodilation and resulting in better cartilage nutrition [39]. This could lead to a decrease in the whole evolutionary-degradative and inflammatory process of the joint, which could lead to an improvement in the clinical symptoms [40; 59]. In line with the anti-inflammatory activity of cucumbers, we found a significant decrease in the plasma levels of IL-1\(\beta\) in the experimental group only. IL-1\(\beta\) is a key pro-inflammatory cytokine involved in the cytokine cascade in pain and inflammatory processes [60; 61]. Moreover, a significant reduction in plasma levels of MMP-3 in the experimental group was observed, whereas, in the placebo group, values of MMP-3 at baseline and at the end of the study were similar. Matrix metalloproteinases (MMPs) are a class of enzymes involved in the degradation of extracellular matrix molecules, and MMP-3 is considered to be of importance in the degradation of articular cartilage. In a study in patients with hip, knee and hand OA, treatment with NSAIDs was associated with a significant reduction in MMP-3 levels [62]. Increased plasma levels of MMP-3 have been reported in patients with knee OA and generalized OA as compared with normal subjects [63]. Moreover, increased levels of plasma and synovial fluid MMP-3 have been detected in patients with hip and knee OA, suggesting that MMP-3 could be used as a potential biomarker of knee OA [64]. The cucumber extract used in this study was associated with an improvement in biomarkers of inflammation as a manifestation of reduced cartilage degradation in knee OA. Some limitations of the study should be considered when interpreting the present results, particularly the reduced sample size and the treatment period, which was restricted to 8 weeks, as well as the reliance on endpoints (subjective and biomarkers) that could be influenced by other confounding factors. In this respect, the inclusion of imaging endpoints in future studies would provide further support to our findings.