{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T12:29:52Z","timestamp":1764937792670,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Health Industry Development Institute (KHIDI)","award":["RS-2023-KH139918"],"award-info":[{"award-number":["RS-2023-KH139918"]}]},{"name":"Ministry of Health and Welfare, Republic of Korea","award":["RS-2023-KH139918"],"award-info":[{"award-number":["RS-2023-KH139918"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is an age-related disease characterized by inflammation, pain, articular cartilage damage, synovitis, and irreversible disability. Gynostemma pentaphyllum (Thunb.) Makino (GP), a herbal medicine traditionally used in East Asia for its anti-inflammatory properties, was investigated for its potential to modulate OA pathology and symptoms. This study evaluated GP\u2019s efficacy in inhibiting pain, functional decline, and cartilage destruction in monosodium iodoacetate-induced OA and acetic acid-induced writhing models. Additionally, the effects of GP on OA-related inflammatory targets were assessed via mRNA and protein expression in rat knee cartilage and lipopolysaccharide-induced RAW 264.7 cells. The GP group demonstrated significant pain relief, functional improvement, and cartilage protection. Notably, GP inhibited key inflammatory mediators, including interleukin (IL)-1\u03b2, IL-6, matrix metalloproteinases (MMP)-3 and MMP-13, cyclooxygenase-2, and prostaglandin E receptor 2, surpassing the effects of active controls. These findings suggest that GP is a promising candidate for disease-modifying OA drugs and warrants further comprehensive studies.<\/jats:p>","DOI":"10.3390\/ijms25179594","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T02:34:06Z","timestamp":1725503646000},"page":"9594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Investigating the Anti-Inflammatory, Analgesic, and Chondroprotective Effects of Gynostemma pentaphyllum (Thunb.) Makino in Osteoarthritis: An In Vitro and In Vivo Study"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1805-4387","authenticated-orcid":false,"given":"Hee-Geun","family":"Jo","sequence":"first","affiliation":[{"name":"Department of Herbal Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si 13120, Republic of Korea"},{"name":"Naturalis Inc., 6 Daewangpangyo-ro, Bundang-gu, Seongnam-si 13549, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8167-049X","authenticated-orcid":false,"given":"Chae Yun","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Herbal Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7073-5113","authenticated-orcid":false,"given":"Yeseul","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Herbal Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunhye","family":"Baek","sequence":"additional","affiliation":[{"name":"RexSoft Inc., 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chanyoon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Herbal Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5306-8795","authenticated-orcid":false,"given":"Ho Sueb","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Acupuncture & Moxibustion Medicine, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1075-0713","authenticated-orcid":false,"given":"Donghun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Herbal Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41413-022-00226-9","article-title":"Current Understanding of Osteoarthritis Pathogenesis and Relevant New Approaches","volume":"10","author":"Tong","year":"2022","journal-title":"Bone Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1481","DOI":"10.1210\/clinem\/dgaa728","article-title":"New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms","volume":"106","author":"Tchkonia","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/s43587-021-00080-0","article-title":"The Economic Value of Targeting Aging","volume":"1","author":"Scott","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102382","DOI":"10.1016\/j.arr.2024.102382","article-title":"Trends and Cross-Country Inequalities in the Global Burden of Osteoarthritis, 1990\u20132019: A Population-Based Study","volume":"99","author":"Cao","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrrheum.2016.136","article-title":"Low-Grade Inflammation as a Key Mediator of the Pathogenesis of Osteoarthritis","volume":"12","author":"Robinson","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.joca.2023.12.005","article-title":"Inflammation in Osteoarthritis: Our View on Its Presence and Involvement in Disease Development over the Years","volume":"32","author":"Blom","year":"2024","journal-title":"Osteoarthr. Cartil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/nm.4000","article-title":"Cellular Senescence in Aging and Age-Related Disease: From Mechanisms to Therapy","volume":"21","author":"Childs","year":"2015","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1038\/s41591-022-01923-y","article-title":"Cellular Senescence and Senolytics: The Path to the Clinic","volume":"28","author":"Chaib","year":"2022","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s12016-022-08941-1","article-title":"Inflammaging and Osteoarthritis","volume":"64","author":"Motta","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s12016-021-08899-6","article-title":"Immunology of Aging: The Birth of Inflammaging","volume":"64","author":"Fulop","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9518","DOI":"10.1111\/jcmm.15669","article-title":"The Emerging Role of Fibroblast-like Synoviocytes-Mediated Synovitis in Osteoarthritis: An Update","volume":"24","author":"Han","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/j.joca.2023.06.005","article-title":"Fundamentals of Osteoarthritis: Inflammatory Mediators in Osteoarthritis","volume":"31","author":"Monteagudo","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41392-023-01330-w","article-title":"Osteoarthritis: Pathogenic Signaling Pathways and Therapeutic Targets","volume":"8","author":"Yao","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e069722","DOI":"10.1136\/bmj-2022-069722","article-title":"Viscosupplementation for Knee Osteoarthritis: Systematic Review and Meta-Analysis","volume":"378","author":"Pereira","year":"2022","journal-title":"BMJ"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1016\/j.joca.2023.05.015","article-title":"Recommendations for the Management of Hip and Knee Osteoarthritis: A Systematic Review of Clinical Practice Guidelines","volume":"31","author":"Gibbs","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.1001\/jama.2018.19319","article-title":"Association of Pharmacological Treatments With Long-Term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-Analysis","volume":"320","author":"Gregori","year":"2018","journal-title":"JAMA"},{"key":"ref_17","first-page":"n2321","article-title":"Effectiveness and Safety of Non-Steroidal Anti-Inflammatory Drugs and Opioid Treatment for Knee and Hip Osteoarthritis: Network Meta-Analysis","volume":"375","author":"Pereira","year":"2021","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.joca.2022.11.005","article-title":"Pharmaceutical Treatment of Osteoarthritis","volume":"31","author":"Richard","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100168","DOI":"10.1016\/j.jtauto.2022.100168","article-title":"Steroid-Induced Osteonecrosis","volume":"5","author":"Motta","year":"2022","journal-title":"J. Transl. Autoimmun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1056\/NEJMoa1905877","article-title":"Physical Therapy versus Glucocorticoid Injection for Osteoarthritis of the Knee","volume":"382","author":"Deyle","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41584-024-01126-4","article-title":"Clinical Phenotypes, Molecular Endotypes and Theratypes in OA Therapeutic Development","volume":"20","author":"Mobasheri","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103488","DOI":"10.1016\/j.drudis.2023.103488","article-title":"New Trends for Osteoarthritis: Biomaterials, Models and Modeling","volume":"28","author":"Manivong","year":"2023","journal-title":"Drug Discov. Today"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.tem.2023.01.005","article-title":"Efficacy Evaluation, Active Ingredients, and Multitarget Exploration of Herbal Medicine","volume":"34","author":"Ren","year":"2023","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1002\/ptr.7935","article-title":"Natural Anti-Inflammatory Products for Osteoarthritis: From Molecular Mechanism to Drug Delivery Systems and Clinical Trials","volume":"37","author":"Su","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101981","DOI":"10.1016\/j.arr.2023.101981","article-title":"Prevention and Treatment of Inflammatory Arthritis with Traditional Chinese Medicine: Underlying Mechanisms Based on Cell and Molecular Targets","volume":"89","author":"Li","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Jo, H.-G., Lee, G.-Y., Baek, C.Y., Song, H.S., and Lee, D. (2020). Analgesic and Anti-Inflammatory Effects of Aucklandia Lappa Root Extracts on Acetic Acid-Induced Writhing in Mice and Monosodium Iodoacetate-Induced Osteoarthritis in Rats. Plants, 10.","DOI":"10.3390\/plants10010042"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jo, H.-G., Baek, C.Y., Kim, D., Lee, D., and Song, H.S. (2023). Stem of Sorbus Commixta Hedl. Extract Inhibits Cartilage Degradation and Arthritic Pain in Experimental Model via Anti-Inflammatory Activity. Nutrients, 15.","DOI":"10.3390\/nu15173774"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jo, H.G., Baek, C.Y., Kim, D., Kim, S., Han, Y., Park, C., Song, H.S., and Lee, D. (2023). Network Analysis, in Vivo, and in Vitro Experiments Identified the Mechanisms by Which Piper Longum L. [Piperaceae] Alleviates Cartilage Destruction, Joint Inflammation, and Arthritic Pain. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1282943"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Jo, H.-G., Baek, C.Y., Lee, J., Hwang, Y., Baek, E., Hwang, J.H., and Lee, D. (2024). Anti-Inflammatory, Analgesic, Functional Improvement, and Chondroprotective Effects of Erigeron Breviscapus (Vant.) Hand.-Mazz. Extract in Osteoarthritis: An In Vivo and In Vitro Study. Nutrients, 16.","DOI":"10.3390\/nu16071035"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jo, H.-G., Baek, C.-Y., Song, H.S., and Lee, D. (2024). Network Pharmacology and Experimental Verifications to Discover Scutellaria Baicalensis Georgi\u2019s Effects on Joint Inflammation, Destruction, and Pain in Osteoarthritis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042127"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13020-024-00899-w","article-title":"Natural Products in Osteoarthritis Treatment: Bridging Basic Research to Clinical Applications","volume":"19","author":"Fang","year":"2024","journal-title":"Chin. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106460","DOI":"10.1016\/j.phrs.2022.106460","article-title":"Clinical Evidence Construction of East Asian Herbal Medicine for Inflammatory Pain in Rheumatoid Arthritis Based on Integrative Data Mining Approach","volume":"185","author":"Jo","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Su, C., Li, N., Ren, R., Wang, Y., Su, X., Lu, F., Zong, R., Yang, L., and Ma, X. (2021). Progress in the Medicinal Value, Bioactive Compounds, and Pharmacological Activities of Gynostemma Pentaphyllum. Molecules, 26.","DOI":"10.3390\/molecules26206249"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.2174\/1568026619666191114104718","article-title":"Medicinal Value and Potential Therapeutic Mechanisms of Gynostemma pentaphyllum (Thunb.) Makino and Its Derivatives: An Overview","volume":"19","author":"Li","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gong, L., Yin, J., Zhang, Y., Huang, R., Lou, Y., Jiang, H., Sun, L., Jia, J., and Zeng, X. (2022). Neuroprotective Mechanisms of Ginsenoside Rb1 in Central Nervous System Diseases. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.914352"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ling, G., Zhang, M., Chen, C., Wang, Y., Gao, Q., Li, J., Yuan, H., Jin, W., Lin, W., and Yang, L. (2024). Progress of Ginsenoside Rb1 in Neurological Disorders. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1280792"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ni, X.-C., Wang, H.-F., Cai, Y.-Y., Yang, D., Alolga, R.N., Liu, B., Li, J., and Huang, F.-Q. (2022). Ginsenoside Rb1 Inhibits Astrocyte Activation and Promotes Transfer of Astrocytic Mitochondria to Neurons against Ischemic Stroke. Redox Biol., 54.","DOI":"10.1016\/j.redox.2022.102363"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.joca.2021.10.009","article-title":"Mitochondrial Quality Control in Cartilage Damage and Osteoarthritis: New Insights and Potential Therapeutic Targets","volume":"30","author":"Liu","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Tudorachi, N.B., Totu, E.E., Fifere, A., Ardeleanu, V., Mocanu, V., Mircea, C., Isildak, I., Smilkov, K., and C\u0103r\u0103u\u015fu, E.M. (2021). The Implication of Reactive Oxygen Species and Antioxidants in Knee Osteoarthritis. Antioxidants, 10.","DOI":"10.3390\/antiox10060985"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"106163","DOI":"10.1016\/j.phrs.2022.106163","article-title":"Rutin Ameliorates Inflammation and Improves Metabolic Function: A Comprehensive Analysis of Scientific Literature","volume":"178","author":"Muvhulawa","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1159\/000451027","article-title":"Rutin Attenuates Oxidative Stress and Proinflammatory Cytokine Level in Adjuvant Induced Rheumatoid Arthritis via Inhibition of NF-\u03baB","volume":"100","author":"Sun","year":"2017","journal-title":"Pharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"117186","DOI":"10.1016\/j.jep.2023.117186","article-title":"Saponins Derived from Gynostemma Pentaphyllum Regulate Triglyceride and Cholesterol Metabolism and the Mechanisms: A Review","volume":"319","author":"Xie","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Chen, X.-B., Yao, C.-L., Hou, J.-R., Nie, M., Li, Y., Wei, W.-L., Zhang, J.-Q., Qu, H., Li, J.-Y., and Bi, Q.-R. (2023). Systematical Characterization of Gypenosides in Gynostemma Pentaphyllum and the Chemical Composition Variation of Different Origins. J. Pharm. Biomed. Anal., 232.","DOI":"10.1016\/j.jpba.2023.115328"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.berh.2018.03.003","article-title":"Osteoarthritis Pain: What Are We Learning from Animal Models?","volume":"31","author":"Miller","year":"2017","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Jimi, E., Huang, F., and Nakatomi, C. (2019). NF-\u03baB Signaling Regulates Physiological and Pathological Chondrogenesis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246275"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2207993120","DOI":"10.1073\/pnas.2207993120","article-title":"NOS Inhibition Reverses TLR2-Induced Chondrocyte Dysfunction and Attenuates Age-Related Osteoarthritis","volume":"120","author":"Shen","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/art.24258","article-title":"Prostaglandin E2 and Its Cognate EP Receptors Control Human Adult Articular Cartilage Homeostasis and Are Linked to the Pathophysiology of Osteoarthritis","volume":"60","author":"Li","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Sun, Q., Zhang, Y., Ding, Y., Xie, W., Li, H., Li, S., Li, Y., and Cai, M. (2022). Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis. Cells, 11.","DOI":"10.3390\/cells11172760"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41584-023-00966-w","article-title":"Matrix Metalloproteinases in Arthritis: Towards Precision Medicine","volume":"19","author":"Grillet","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5325","DOI":"10.1039\/D3TB02871B","article-title":"On-Demand Release of a Selective MMP-13 Blocker from an Enzyme-Responsive Injectable Hydrogel Protects Cartilage from Degenerative Progression in Osteoarthritis","volume":"12","author":"Roy","year":"2024","journal-title":"J. Mater. Chem. B"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1421S","DOI":"10.1177\/1947603520946385","article-title":"A Preliminary Study of Combined Detection of COMP, TIMP-1, and MMP-3 in Synovial Fluid: Potential Indicators of Osteoarthritis Progression","volume":"13","author":"Spakova","year":"2021","journal-title":"Cartilage"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.jep.2013.06.027","article-title":"Toxicity Evaluation of Standardized Extract of Gynostemma Pentaphyllum Makino","volume":"149","author":"Chiranthanut","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Du Sert, N.P., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE Guidelines 2.0: Updated Guidelines for Reporting Animal Research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1002\/art.1780400917","article-title":"Mono-iodoacetate-induced Experimental Osteoarthritis. A Dose-response Study of Loss of Mobility, Morphology, and Biochemistry","volume":"40","author":"Guingamp","year":"1997","journal-title":"Arthritis Rheum."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Tian, Y., Onodera, T., Terkawi, M.A., Iwasaki, K., Hishimura, R., Liang, D., Miyazaki, T., and Iwasaki, N. (2021). Local Administration of Low-Dose Nerve Growth Factor Antibody Reduced Pain in a Rat Osteoarthritis Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052552"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:48:45Z","timestamp":1760111325000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,4]]},"references-count":55,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25179594"],"URL":"https:\/\/doi.org\/10.3390\/ijms25179594","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,9,4]]}}}