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      Selection and Investigation of a Primate Model of Spontaneous Degenerative Knee Osteoarthritis, the Cynomolgus Monkey ( Macaca Fascicularis)


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          The aim of this study was to identify a primate model of degenerative knee osteoarthritis (KOA) that may be more relevant for research studies on degenerative KOA in humans.


          Sixteen specific-pathogen-free (SPF) male cynomolgus monkeys ( Macaca fascicularis) were divided into group A (n=8), an old group (22.0–25.3 years of age), and group B (n=8), a young group (3.0–5.2 years of age). For each primate, the behavior was observed, knee circumference was measured, knee joint X-rays were performed, and peripheral blood white blood cell (WBC) counts were measured, and the Kellgren and Lawrence (K-L) system was used for the classification of osteoarthritis. An enzyme-linked immunoassay (ELISA) was performed on knee joint fluid to measure levels of interleukin (IL)-1β, transforming growth factor (TGF)-β1, and matrix metalloproteinase (MMP)13. Changes in articular cartilage were evaluated using the Brittberg score and the Mankin histopathology grading score, respectively. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot were used to measure the expression of the NOTCH3, JAG1, and ACAN genes in knee cartilage specimens, and the findings in the two groups of primates were compared.


          Seven old aged primates in group A were compared with group B, and showed significant differences in WBC count, synovial fluid IL-1β, TGF-β1, and MMP13 levels, expression levels of the NOTCH3, JAG1, and ACAN genes in knee cartilage specimens, and in the Brittberg and Mankin scores (all, P<0.05).


          Cynomolgus monkeys ( Macaca fascicularis) might be a model for age-related degenerative KOA.

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          The role of cytokines in osteoarthritis pathophysiology.

          Morphological changes observed in OA include cartilage erosion as well as a variable degree of synovial inflammation. Current research attributes these changes to a complex network of biochemical factors, including proteolytic enzymes, that lead to a breakdown of the cartilage macromolecules. Cytokines such as IL-1 and TNF-alpha produced by activated synoviocytes, mononuclear cells or by articular cartilage itself significantly up-regulate metalloproteinases (MMP) gene expression. Cytokines also blunt chondrocyte compensatory synthesis pathways required to restore the integrity of the degraded extrecellular matrix (ECM). Moreover, in OA synovium, a relative deficit in the production of natural antagonists of the IL-1 receptor (IL-1Ra) has been demonstrated, and could possibly be related to an excess production of nitric oxide in OA tissues. This, coupled with an upregulation in the receptor level, has been shown to be an additional enhancer of the catabolic effect of IL-1 in this disease.IL-1 and TNF-alpha significantly up-regulate MMP-3 steady-state mRNA derived from human synovium and chondrocytes. The neutralization of IL-1 and/or TNF-alpha up-regulation of MMP gene expression appears to be a logical development in the potential medical therapy of OA. Indeed, recombinant IL-1receptor antagonists (ILRa) and soluble IL-1 receptor proteins have been tested in both animal models of OA for modification of OA progression. Soluble IL-1Ra suppressed MMP-3 transcription in the rabbit synovial cell line HIG-82. Experimental evidence showing that neutralizing TNF-alpha suppressed cartilage degradation in arthritis also support such strategy. The important role of TNF-alpha in OA may emerge from the fact that human articular chondrocytes from OA cartilage expressed a significantly higher number of the p55 TNF-alpha receptor which could make OA cartilage particularly susceptible to TNF-alpha degradative stimuli. In addition, OA cartilage produces more TNF-alpha and TNF anglealpha convertase enzyme (TACE) mRNA than normal cartilage. By analogy, an inhibitor to the p55 TNF-alpha receptor may also provide a mechanism for abolishing TNF-alpha-induced degradation of cartilage ECM by MMPs. Since TACE is the regulator of TNF-alpha activity, limiting the activity of TACE might also prove efficacious in OA. IL-1 and TNF-alpha inhibition of chondrocyte compensatory biosynthesis pathways which further compromise cartilage repair must also be dealt with, perhaps by employing stimulatory agents such as transforming growth factor-beta or insulin-like growth factor-I. Certain cytokines have antiinflammatory properties. Three such cytokines - IL-4, IL-10, and IL-13 - have been identified as able to modulate various inflammatory processes. Their antiinflammatory potential, however, appears to depend greatly on the target cell. Interleukin-4 (IL-4) has been tested in vitro in OA tissue and has been shown to suppress the synthesis of both TNF-alpha and IL-1beta in the same manner as low-dose dexamethasone. Naturally occurring antiinflammatory cytokines such as IL-10 inhibit the synthesis of IL-1 and TNF-alpha and can be potential targets for therapy in OA. Augmenting inhibitor production in situ by gene therapy or supplementing it by injecting the recombinant protein is an attractive therapeutic target, although an in vivo assay in OA is not available, and its applicability has yet to be proven. Similarly, IL-13 significantly inhibits lipopolysaccharide (LPS)-induced TNF-alpha production by mononuclear cells from peripheral blood, but not in cells from inflamed synovial fluid. IL-13 has important biological activities: inhibition of the production of a wide range of proinflammatory cytokines in monocytes/macrophages, B cells, natural killer cells and endothelial cells, while increasing IL-1Ra production. In OA synovial membranes treated with LPS, IL-13 inhibited the synthesis of IL-1beta, TNF-alpha and stromelysin, while increasing IL-1Ra production.In summary, modulation of cytokines that control MMP gene up-regulation would appear to be fertile targets for drug development in the treatment of OA. Several studies illustrate the potential importance of modulating IL-1 activity as a means to reduce the progression of the structural changes in OA. In the experimental dog and rabbit models of OA, we have demonstrated that in vivo intraarticular injections of the IL-Ra gene can prevent the progression of structural changes in OA. Future directions in the research and treatment of osteoarthritis (OA) will be based on the emerging picture of pathophysiological events that modulate the initiation and progression of OA.
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            Projections of US prevalence of arthritis and associated activity limitations.

            To update the projected prevalence of self-reported, doctor-diagnosed arthritis and arthritis-attributable activity limitations among US adults ages 18 years and older from 2005 through 2030. Baseline age- and sex-specific prevalence rates of arthritis and activity limitation, using the latest surveillance case definitions, were estimated from the 2003 National Health Interview Survey, which is an annual, cross-sectional, population-based health interview survey of approximately 31,000 adults. These estimates were used to calculate projected arthritis prevalence and activity limitations for 2005-2030 using future population projections obtained from the US Census Bureau. The prevalence of self-reported, doctor-diagnosed arthritis is projected to increase from 47.8 million in 2005 to nearly 67 million by 2030 (25% of the adult population). By 2030, 25 million (9.3% of the adult population) are projected to report arthritis-attributable activity limitations. In 2030, >50% of arthritis cases will be among adults older than age 65 years. However, working-age adults (45-64 years) will account for almost one-third of cases. By 2030, the number of US adults with arthritis and its associated activity limitation is expected to increase substantially, resulting in a large impact on individuals, the health care system, and society in general. The growing epidemic of obesity may also significantly contribute to the future burden of arthritis. Improving access and availability of current clinical and public health interventions aimed at improving quality of life among persons with arthritis through lifestyle changes and disease self-management may help lessen the long-term impact.
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              Current research on pharmacologic and regenerative therapies for osteoarthritis

              Osteoarthritis (OA) is a degenerative joint disorder commonly encountered in clinical practice, and is the leading cause of disability in elderly people. Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers, OA is a challenging disease with limited treatment options. Traditional pharmacologic therapies such as acetaminophen, non-steroidal anti-inflammatory drugs, and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events. Current research focuses on the development of new OA drugs (such as sprifermin/recombinant human fibroblast growth factor-18, tanezumab/monoclonal antibody against β-nerve growth factor), which aims for more effectiveness and less incidence of adverse effects than the traditional ones. Furthermore, regenerative therapies (such as autologous chondrocyte implantation (ACI), new generation of matrix-induced ACI, cell-free scaffolds, induced pluripotent stem cells (iPS cells or iPSCs), and endogenous cell homing) are also emerging as promising alternatives as they have potential to enhance cartilage repair, and ultimately restore healthy tissue. However, despite currently available therapies and research advances, there remain unmet medical needs in the treatment of OA. This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations.

                Author and article information

                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                01 July 2018
                : 24
                : 4516-4527
                [1 ]Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China
                [2 ]College of Nursing, Affiliated to Southwest Medical University, Luzhou, Sichuan, P.R. China
                Author notes
                Corresponding Author: Shijie Fu, e-mail: fushijieggj@ 123456126.com

                Study Design


                Data Collection


                Statistical Analysis


                Data Interpretation


                Manuscript Preparation


                Literature Search


                Funds Collection


                These authors contributed equally to this study

                © Med Sci Monit, 2018

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

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