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      Expression of matrix metalloproteinases and components of the endocannabinoid system in the knee joint are associated with biphasic pain progression in a rat model of osteoarthritis

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          Abstract

          Matrix metalloproteinases (MMPs) are considered important in articular cartilage breakdown during osteoarthritis (OA). Similarly, the endocannabinoid system (ECS) is implicated in joint function and modulation of nociceptive processing. Functional interplay between ECS and MMPs has been recently indicated. Here, we tested if changes in the expression of selected MMPs and major ECS elements temporally correlate with the intensity of OA-related pain. Knee OA was induced in male Wistar rats by intra-articular sodium monoiodoacetate injection. OA-like pain behavior was tested using the dynamic weight bearing. Joint tissue samples at different time points after OA induction were subjected to gene (quantitative polymerase chain reaction) and protein (Western blot) expression analyses. Monoiodoacetate-induced nocifensive responses in rats showed a biphasic progression pattern. The alterations in expression of selected MMPs elegantly corresponded to the two-stage development of OA pain. The most substantial changes in the expression of the ECS system were revealed at a later stage of OA progression. Alterations within ECS are involved in the process of adaptation to persistent painful stimuli. The accumulation of MMPs in osteoarthritic cartilage may have a role in the biphasic progression of OA-related pain. Temporal association of changes in ECS and MMPs expression shows a potential therapeutic approach that utilizes the concept of combining indirect ECS-mediated MMP inhibition and ECS modulation of pain transduction.

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          Most cited references 50

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          Ethical guidelines for investigations of experimental pain in conscious animals.

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            Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage.

            We demonstrate the direct involvement of increased collagenase activity in the cleavage of type II collagen in osteoarthritic human femoral condylar cartilage by developing and using antibodies reactive to carboxy-terminal (COL2-3/4C(short)) and amino-terminal (COL2-1/4N1) neoepitopes generated by cleavage of native human type II collagen by collagenase matrix metalloproteinase (MMP)-1 (collagenase-1), MMP-8 (collagenase-2), and MMP-13 (collagenase-3). A secondary cleavage followed the initial cleavage produced by these recombinant collagenases. This generated neoepitope COL2-1/4N2. There was significantly more COL2-3/4C(short) neoepitope in osteoarthritis (OA) compared to adult nonarthritic cartilages as determined by immunoassay of cartilage extracts. A synthetic preferential inhibitor of MMP-13 significantly reduced the unstimulated release in culture of neoepitope COL2-3/4C(short) from human osteoarthritic cartilage explants. These data suggest that collagenase(s) produced by chondrocytes is (are) involved in the cleavage and denaturation of type II collagen in articular cartilage, that this is increased in OA, and that MMP-13 may play a significant role in this process.
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              Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis.

              To describe an in vivo model in the rat in which change in weight distribution is used as a measure of disease progression and efficacy of acetaminophen and two nonsteroidal anti-inflammatory drugs (NSAIDs) in a model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). Intra-articular injections of MIA and saline were administered to male Wistar rats (175-200 g) into the right and left knee joints, respectively. Changes in hind paw weight distribution between the right (osteoarthritic) and left (contralateral control) limbs were utilized as an index of joint discomfort. Acetaminophen and two archetypal, orally administered NSAIDs, naproxen and rofecoxib, were examined for their ability to decrease MIA-induced change in weight distribution. A concentration-dependent increase in change in hind paw weight distribution was noted after intra-articular injection of MIA. Both naproxen and rofecoxib demonstrated the capacity to significantly (P<0.05) decrease hind paw weight distribution in a dose-dependent fashion, indicating that the change in weight distribution associated with MIA injection is susceptible to pharmacological intervention. The determination of differences in hind paw weight distribution in the rat MIA model of OA is a technically straightforward, reproducible method that is predictive of the effects of anti-inflammatory and analgesic agents. This system may be useful for the discovery of novel pharmacologic agents in human OA.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2017
                21 August 2017
                : 10
                : 1973-1989
                Affiliations
                Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
                Author notes
                Correspondence: Katarzyna Starowicz, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31–343 Krakow, Poland, Tel +48 12 662 3206, Fax +48 12 637 4500, Email starow@ 123456if-pan.krakow.pl
                Article
                jpr-10-1973
                10.2147/JPR.S132682
                5573042
                © 2017 Pajak et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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