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      Chondroprotective Mechanism of Eucommia ulmoides Oliv.- Glycyrrhiza uralensis Fisch. Couplet Medicines in Knee Osteoarthritis via Experimental Study and Network Pharmacology Analysis


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          Knee osteoarthritis (KOA) is the primary prevalent disabling joint disorder among osteoarthritis (OA), and there is no particularly effective treatment at the clinic. Traditional Chinese medicine (TCM) herbs, such as Eucommia ulmoides Oliv. and Glycyrrhiza uralensis Fisch. (E.G.) couplet medicines, have been reported to exhibit beneficial health effects on KOA, exact mechanism of E.G. nevertheless is not fully elucidated.


          We assess the therapeutic effects of E.G. on KOA and explore its underlying molecular mechanism.


          UPLC-Q-TOF/MS technique was used to analyze the active chemical constituents of E.G. The destabilization of the medial meniscus model (DMM) was employed to evaluate the chondroprotective action of E.G. in KOA mice using histomorphometry, μCT, behavioral testing and immunohistochemical staining. Additionally, network pharmacology and molecular docking were used to predict potential targets for anti-KOA activities of E.G., which was further verified through in vitro experiments.


          In vivo studies have shown that E.G. could significantly ameliorate DMM-induced KOA phenotypes including subchondral bone sclerosis, cartilage degradation, gait abnormality and thermal pain reaction sensibility. E.G. treatment could also promote extracellular matrix synthesis to protect articular chondrocytes, which was indicated by Col2 and Aggrecan expressions, as well as reducing matrix degradation by inhibiting MMP13 expression. Interestingly, network pharmacologic analysis showed that PPARG might be a therapeutic center. Further study proved that E.G.-containing serum (EGS) could up-regulate PPARG mRNA level in IL-1β-induced chondrocytes. Notably, significant effects of EGS on the increment of anabolic gene expressions ( Col2, Aggrecan) and the decrement of catabolic gene expressions ( MMP13, Adamts5) in KOA chondrocytes were abolished due to the silence of PPARG.


          E.G. played a chondroprotective role in anti-KOA by inhibiting extracellular matrix degradation, which might be related to PPARG.

          Graphical Abstract

          Most cited references43

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          Osteoarthritis is a leading cause of disability and source of societal cost in older adults. With an ageing and increasingly obese population, this syndrome is becoming even more prevalent than in previous decades. In recent years, we have gained important insights into the cause and pathogenesis of pain in osteoarthritis. The diagnosis of osteoarthritis is clinically based despite the widespread overuse of imaging methods. Management should be tailored to the presenting individual and focus on core treatments, including self-management and education, exercise, and weight loss as relevant. Surgery should be reserved for those that have not responded appropriately to less invasive methods. Prevention and disease modification are areas being targeted by various research endeavours, which have indicated great potential thus far. This narrative Seminar provides an update on the pathogenesis, diagnosis, management, and future research on osteoarthritis for a clinical audience.
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            Osteoarthritis is a major source of pain, disability, and socioeconomic cost worldwide. The epidemiology of the disorder is complex and multifactorial, with genetic, biological, and biomechanical components. Aetiological factors are also joint specific. Joint replacement is an effective treatment for symptomatic end-stage disease, although functional outcomes can be poor and the lifespan of prostheses is limited. Consequently, the focus is shifting to disease prevention and the treatment of early osteoarthritis. This task is challenging since conventional imaging techniques can detect only quite advanced disease and the relation between pain and structural degeneration is not close. Nevertheless, advances in both imaging and biochemical markers offer potential for diagnosis and as outcome measures for new treatments. Joint-preserving interventions under development include lifestyle modification and pharmaceutical and surgical modalities. Some show potential, but at present few have proven ability to arrest or delay disease progression.
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              Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints. Primary OA results from a combination of risk factors, with increasing age and obesity being the most prominent. The concept of the pathophysiology is still evolving, from being viewed as cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship between local and systemic factors modulates its clinical and structural presentations, leading to a common final pathway of joint destruction. Pharmacological treatments are mostly related to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory agencies. Identifying phenotypes of patients will enable the detection of the disease in its early stages as well as distinguish individuals who are at higher risk of progression, which in turn could be used to guide clinical decision making and allow more effective and specific therapeutic interventions to be designed. This Primer is an update on the progress made in the field of OA epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention and disease management.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                27 February 2023
                : 17
                : 633-646
                [1 ]College of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou, People’s Republic of China
                [2 ]Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University , Hangzhou, People’s Republic of China
                [3 ]The First College of Clinical Medicine, Zhejiang Chinese Medical University , Hangzhou, People’s Republic of China
                [4 ]Department of Orthopedic Joint Surgery, Hangzhou Fuyang Hospital of TCM Orthopaedics and Traumatology , Hangzhou, People’s Republic of China
                [5 ]Department of Orthopedic Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University , Hangzhou, People’s Republic of China
                Author notes
                Correspondence: Chunchun Zhang, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel/Fax +86 571-86613684, Email 20081026@zcmu.edu.cn
                Fanzhu Li, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel/Fax +86 571-86613684, Email lifanzhu@zcmu.edu.cn

                These authors contributed equally to this work

                © 2023 Wang 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 11 November 2022
                : 07 February 2023
                Page count
                Figures: 6, Tables: 2, References: 43, Pages: 14
                Funded by: Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: State Administration of Traditional Chinese Medicine of Zhejiang Province;
                This study was partially supported by Natural Science Foundation of China (Grant no. 81973869 and 82104889), Zhejiang Provincial Natural Science Foundation of China (Grant no. LY22H270005), the State Administration of Traditional Chinese Medicine of Zhejiang Province (Grant no. 2021ZZ014), the Research Project of Zhejiang Chinese Medical University (Grant no. 2022JKZKTS32).
                Original Research

                Pharmacology & Pharmaceutical medicine
                couplet medicines,uplc-q-tof/ms,network pharmacology,cartilage degeneration,knee osteoarthritis,pparg


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