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      Seomae mugwort and jaceosidin attenuate osteoarthritic cartilage damage by blocking IκB degradation in mice

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          Abstract

          Seomae mugwort, a Korean native variety of Artemisia argyi, exhibits physiological effects against various diseases. However, its effects on osteoarthritis (OA) are unclear. In this study, a Seomae mugwort extract prevented cartilage destruction in an OA mouse model. In vitro and ex vivo analyses revealed that the extract suppressed MMP3, MMP13, ADAMTS4 and ADAMTS5 expression induced by IL‐1β, IL‐6 and TNF‐α and inhibited the loss of extracellular sulphated proteoglycans. In vivo analysis revealed that oral administration of the extract suppressed DMM‐induced cartilage destruction. We identified jaceosidin in Seomae mugwort and showed that this compound decreased MMP3, MMP13, ADAMTS4 and ADAMTS5 expression levels, similar to the action of the Seomae mugwort extract in cultured chondrocytes. Interestingly, jaceosidin and eupatilin combined had similar effects to Seomae mugwort in the DMM‐induced OA model. Induction of IκB degradation by IL‐1β was blocked by the extract and jaceosidin, whereas JNK phosphorylation was only suppressed by the extract. These results suggest that the Seomae mugwort extract and jaceosidin can attenuate cartilage destruction by suppressing MMPs, ADAMTS4/5 and the nuclear factor‐κB signalling pathway by blocking IκB degradation. Thus, the findings support the potential application of Seomae mugwort, and particularly jaceosidin, as natural therapeutics for OA.

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          Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction.

          Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2alpha expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2alpha causes cartilage destruction by regulating crucial catabolic genes.
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            MMP13 is a critical target gene during the progression of osteoarthritis

            Introduction Osteoarthritis (OA) is a degenerative joint disease affecting a large population of people. The mechanism of this highly prevalent disease is not fully understood. Currently there is no effective disease-modifying treatment for OA. The purpose of this study was two-fold: 1) to investigate the role of MMP13 in the development of OA; and 2) to evaluate the efficacy of the MMP13 inhibitor CL82198 as a pharmacologic treatment for preventing OA progression. Methods To investigate the role of the endogenous Mmp13 gene in OA development, tamoxifen was administered to two-week-old Col2CreER;Mmp13fx/fx (Mmp13Col2ER ) and Cre-negative control mice for five days. OA was induced by meniscal-ligamentous injury (MLI) when the mice were 10 weeks old and MLI or sham-operated joints were harvested 4, 8, 12, or 16 weeks after surgery. To evaluate the efficacy of CL82198, MLI surgery was performed on 10-week-old wild type mice. CL82198 or saline was administered to the mice daily beginning immediately after the surgery for up to 16 weeks. The joint tissues collected from both experiments were evaluated by cartilage grading, histology/histomorphometry, immunohistochemistry (IHC), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The ability of CL82198 to inhibit MMP13 activity in vitro was confirmed by ELISA. Results The OA progression was decelerated in Mmp13Col2ER mice 8, 12, and 16 weeks post-surgery. Cartilage grading by blinded observers confirmed decreased articular cartilage degeneration in Mmp13Col2ER mice at 8, 12 and 16 weeks compared to Cre-negative mice. Histomorphometric analysis demonstrated that Mmp13Col2ER mice had a higher articular cartilage area and thickness at 12 and 16 weeks post-surgery compared to the control mice. Results of IHC revealed greater type II collagen and proteoglycan expression in Mmp13Col2ER mice. Chondrocyte apoptosis, as determined by TUNEL staining, was higher in control mice compared to Mmp13Col2ER mice. CL82198 inhibited MMP13 activity in conditioned media from vehicle (> 85%) or bone morphogenetic protein 2 (BMP2)-treated (> 90%) primary murine sternal chondrocytes. Intraperitoneal injection of CL82198 decelerated MLI-induced OA progression, increased type II collagen and proteoglycan levels, and inhibited chondrocyte apoptosis compared to saline treatment as determined by OA grading, histology, histomorphometry, IHC, and TUNEL staining, respectively. Conclusions Mmp13 is critical for OA progression and pharmacologic inhibition of MMP13 is an effective strategy to decelerate articular cartilage loss in a murine model of injury-induced knee OA.
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              Role of Chondrocytes in Cartilage Formation, Progression of Osteoarthritis and Cartilage Regeneration

              Articular cartilage (AC) covers the diarthrodial joints and is responsible for the mechanical distribution of loads across the joints. The majority of its structure and function is controlled by chondrocytes that regulate Extracellular Matrix (ECM) turnover and maintain tissue homeostasis. Imbalance in their function leads to degenerative diseases like Osteoarthritis (OA). OA is characterized by cartilage degradation, osteophyte formation and stiffening of joints. Cartilage degeneration is a consequence of chondrocyte hypertrophy along with the expression of proteolytic enzymes. Matrix Metalloproteinases (MMPs) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are an example of these enzymes that degrade the ECM. Signaling cascades involved in limb patterning and cartilage repair play a role in OA progression. However, the regulation of these remains to be elucidated. Further the role of stem cells and mature chondrocytes in OA progression is unclear. The progress in cell based therapies that utilize Mesenchymal Stem Cell (MSC) infusion for cartilage repair may lead to new therapeutics in the long term. However, many questions are unanswered such as the efficacy of MSCs usage in therapy. This review focuses on the role of chondrocytes in cartilage formation and the progression of OA. Moreover, it summarizes possible alternative therapeutic approaches using MSC infusion for cartilage restoration.
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                Author and article information

                Contributors
                totoro69@korea.kr
                spyun@gnu.ac.kr
                yangsy@ajou.ac.kr
                rkdflwnd@aumc.ac.kr
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                11 June 2020
                July 2020
                : 24
                : 14 ( doiID: 10.1111/jcmm.v24.14 )
                : 8126-8137
                Affiliations
                [ 1 ] Department of Biomedical Sciences Ajou University Graduate School of Medicine Suwon Korea
                [ 2 ] Department of Pharmacology Ajou University School of Medicine Suwon Korea
                [ 3 ] CIRNO Sungkyunkwan University Suwon Korea
                [ 4 ] Department of Medicinal Crop Research National Institute of Horticultural and Herbal Science Rural Development Administration Eumseong Korea
                [ 5 ] Department of Pharmacology and Convergence Medical Science Institute of Health Science, School of Medicine, Gyeongsang National University Jinju Korea
                Author notes
                [*] [* ] Correspondence

                Siyoung Yang, Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Department of Pharmacology, Ajou University School of medicine,164 World cup‐ro, Yeongtong‐gu, Suwon 16499, Korea.

                Emails: yangsy@ 123456ajou.ac.kr

                Li‐Jung Kang, Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Department of Pharmacology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong‐gu, Suwon 16499, Korea.

                Email: rkdflwnd@ 123456aumc.ac.kr

                Seung Pil Yun, Department of Pharmacology, Gyeongsang National University School of Medicine, Jinju 52727, Korea.Department of Pharmacology and Convergence Medical Science, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju 52727, Korea.

                Email: spyun@ 123456gnu.ac.kr

                Yu Su Shin, Department of Medicinal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Bisanro 92, Eumseong, Chungbuk 27709, Korea.

                Email: totoro69@ 123456korea.kr

                Author information
                https://orcid.org/0000-0003-1843-4555
                Article
                JCMM15471
                10.1111/jcmm.15471
                7348148
                32529755
                ae58b90a-e1ab-4f04-839c-fef525f03e97
                © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 November 2019
                : 01 May 2020
                : 12 May 2020
                Page count
                Figures: 5, Tables: 2, Pages: 12, Words: 7351
                Funding
                Funded by: National Research Foundation of Korea , open-funder-registry 10.13039/501100003725;
                Award ID: 2018R1C1B6007038
                Award ID: 2019R1A2B5B03100464
                Award ID: 2019R1I1A3A01061034
                Award ID: SRC2017R1A5A1014560
                Funded by: Rural Development Administration , open-funder-registry 10.13039/501100003627;
                Award ID: PJ01330503
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:10.07.2020

                Molecular medicine
                cartilage destruction,iκb,jaceosidin,matrix metalloproteinase,nuclear factor‐kappa b,osteoarthritis,seomae mugwort

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