{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T17:09:56Z","timestamp":1780938596956,"version":"3.54.1"},"reference-count":53,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,19]],"date-time":"2025-01-19T00:00:00Z","timestamp":1737244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["MOST 113-2314-B-281-001-MY3"],"award-info":[{"award-number":["MOST 113-2314-B-281-001-MY3"]}]},{"name":"Ministry of Science and Technology","award":["MOST 111-2314-B-281-010-MY2"],"award-info":[{"award-number":["MOST 111-2314-B-281-010-MY2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Knee osteoarthritis (OA) is a common and debilitating disorder marked by joint degradation, inflammation, and persistent pain. This study examined the possible therapeutic effects of curcumin and vitamin D on OA progression and pain in a rat knee OA model by anterior cruciate ligament transection and meniscectomy (ACLT + MMx). Methods: Male Wistar rats were categorized into five groups: control, curcumin-treated (100 mg\/kg\/day), vitamin D-treated (25 \u00b5g\/kg\/day), a combination of vitamin D and curcumin, and sham-operated. All supplements were administered orally on a daily basis for 12 weeks. Pain behaviors were assessed, serum biomarkers were measured, and knee histology was examined. Results: Both curcumin and vitamin D independently reduced pain, while the combined group exhibited better analgesic effects. Serum inflammatory cytokines demonstrated a decrease in pro-inflammatory cytokines and an elevation in anti-inflammatory cytokine interleukin-10 (IL-10) in the supplement groups. The antioxidative markers were partially recovered by curcumin and vitamin D supplement. However, the oxidative stress marker Cartilage Oligomeric Matrix Protein (COMP) was significantly reduced. Histology analysis revealed a preservation of joint architecture and cartilage integrity and decreased synovium inflammation in the groups treated with curcumin and vitamin D. Conclusions: Our findings indicate a dual mechanism that encompasses the role of anti-inflammation and antioxidation on knee OA progression and pain reduction, underscoring the potential of these natural chemicals as therapeutic agents for knee OA; curcumin and vitamin D supplement may be added in delaying knee OA progression and associated pain management in clinical patient care.<\/jats:p>","DOI":"10.3390\/nu17020349","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T09:11:13Z","timestamp":1737364273000},"page":"349","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Curcumin and Vitamin D Supplement Attenuates Knee Osteoarthritis Progression in ACLT + MMx Rat Model: Effect on Cartilage Protection and Pain Reduction"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0183-2542","authenticated-orcid":false,"given":"Lokesh Kumar","family":"Mende","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Cathay General Hospital, Taipei 280, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5018-3736","authenticated-orcid":false,"given":"Yaswanth","family":"Kuthati","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Cathay General Hospital, Taipei 280, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-9950","authenticated-orcid":false,"given":"Chih-Shung","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Cathay General Hospital, Taipei 280, Taiwan"},{"name":"National Defense Medical Center, Institute of Medical Sciences, Taipei 280, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1001\/jama.2017.4392","article-title":"Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999\u20132014","volume":"317","author":"Rooney","year":"2017","journal-title":"JAMA-J. Am. Med. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Fracchia, K.M., Pai, C.Y., and Walsh, C.M. (2013). Modulation of T cell metabolism and function through calcium signaling. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00324"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1007\/s11999-008-0543-6","article-title":"Etiology of Ankle Osteoarthritis","volume":"467","author":"Valderrabano","year":"2009","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s00264-017-3414-5","article-title":"Differences in type II collagen turnover of osteoarthritic human knee and ankle joints","volume":"41","author":"Aurich","year":"2017","journal-title":"Int. Orthop."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.lfs.2017.09.022","article-title":"Inhibition of the TGF-beta 1\/Smad signaling pathway protects against cartilage injury and osteoarthritis in a rat model","volume":"189","author":"Wang","year":"2017","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.joca.2009.06.008","article-title":"TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis Modulation and integration of signaling pathways through receptor-Smads","volume":"17","author":"Davidson","year":"2009","journal-title":"Osteoarthr. Cartil."},{"key":"ref_7","first-page":"7224","article-title":"Effect of GGCX on the differentiation function of osteoporosis bone marrow mesenchymal stem cells through regulating TGF beta\/smad signaling pathway","volume":"23","author":"Wang","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.joca.2008.02.015","article-title":"The cartilage chondrolytic mechanism of fibronectin fragments involves MAP kinases: Comparison of three fragments and native fibronectin","volume":"16","author":"Ding","year":"2008","journal-title":"Osteoarthr. Cartil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1021\/bm500620e","article-title":"Control Hydrogel-Hyaluronic Acid Aggregation toward the Design of Biomimetic Superlubricants","volume":"15","author":"Seekell","year":"2014","journal-title":"Biomacromolecules"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhang, F., Xu, M., Yang, Q., Hua, B., Xia, B., Lin, Z., Xiao, X., Monahan, P.E., and Sun, J. (2020). A Translational Study of TNF-Alpha Antagonists as an Adjunctive Therapy for Preventing Hemophilic Arthropathy. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010075"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s11926-021-01007-9","article-title":"Fatty Acids and Oxylipins in Osteoarthritis and Rheumatoid Arthritis\u2014A Complex Field with Significant Potential for Future Treatments","volume":"23","author":"Mustonen","year":"2021","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Oliviero, F., Sfriso, P., Scanu, A., Fiocco, U., Spinella, P., and Punzi, L. (2013). Epigallocatechin-3-gallate reduces inflammation induced by calcium pyrophosphate crystals in vitro. Front. Pharmacol., 4.","DOI":"10.3389\/fphar.2013.00051"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/MAJ.0b013e3182579dc6","article-title":"Reactive Oxygen Species: The 2-Edged Sword of Osteoarthritis","volume":"344","author":"Li","year":"2012","journal-title":"Am. J. Med. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1021\/acsbiomaterials.1c00005","article-title":"Facile Synthesis of Hollow MnO2 Nanoparticles for Reactive Oxygen Species Scavenging in Osteoarthritis","volume":"7","author":"Chen","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"128147","DOI":"10.1016\/j.cej.2020.128147","article-title":"Reactive oxygen species-responsive and scavenging polyurethane nanoparticles for treatment of osteoarthritis in vivo","volume":"409","author":"Zhang","year":"2021","journal-title":"Chem. Eng. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/j.1741-6612.2010.00500.x","article-title":"Levels of reactive oxygen metabolites in patients with knee osteoarthritis","volume":"30","author":"Kotani","year":"2011","journal-title":"Australas. J. Ageing"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.joca.2005.04.002","article-title":"Oxygen and reactive oxygen species in cartilage degradation: Friends or foes?","volume":"13","author":"Henrotin","year":"2005","journal-title":"Osteoarthr. Cartil."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13075-021-02502-1","article-title":"Early detection of osteoarthritis in the rat with an antibody specific to type II collagen modified by reactive oxygen species","volume":"23","author":"Gigout","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Shen, C., Gao, M., Chen, H., Zhan, Y., Lan, Q., Li, Z., Xiong, W., Qin, Z., Zheng, L., and Zhao, J. (2021). Reactive oxygen species (ROS)-responsive nanoprobe for bioimaging and targeting therapy of osteoarthritis. J. Nanobiotechnol., 19.","DOI":"10.1186\/s12951-021-01136-4"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1016\/j.joca.2018.08.014","article-title":"The role of NOX2-derived reactive oxygen species in collagenase-induced osteoarthritis","volume":"26","author":"Kruisbergen","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"745","DOI":"10.2147\/JIR.S297166","article-title":"Engeletin Protects Against TNF-alpha-Induced Apoptosis and Reactive Oxygen Species Generation in Chondrocytes and Alleviates Osteoarthritis in vivo","volume":"14","author":"Wang","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1053\/joca.2002.0789","article-title":"Regulation by reactive oxygen species of interleukin-1 beta, nitric oxide and prostaglandin E-2 production by human chondrocytes","volume":"10","author":"Reginster","year":"2002","journal-title":"Osteoarthr. Cartil."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.jab.2016.05.001","article-title":"Carnosol ameliorates monosodium iodoacetate-induced osteoarthritis by targeting NF-kappa B and Nrf-2 in primary rat chondrocytes","volume":"14","author":"Wang","year":"2016","journal-title":"J. Appl. Biomed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jsbmb.2017.01.022","article-title":"Skeletal muscle vitamin D in patients with end stage osteoarthritis of the knee","volume":"173","author":"Mor","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e4670","DOI":"10.7717\/peerj.4670","article-title":"Association between vitamin D concentrations and knee pain in patients with osteoarthritis","volume":"6","author":"Cakar","year":"2018","journal-title":"PeerJ"},{"key":"ref_26","first-page":"CD004376","article-title":"Exercise for osteoarthritis of the knee","volume":"2024","author":"Lawford","year":"2024","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"303","DOI":"10.5606\/tjr.2011.048","article-title":"An Investigation Into the Relationship Between Taq1 and Apa1 Polymorphisms of the Vitamin D Receptor Gene and the Development of Osteoarthritis","volume":"26","author":"Bayram","year":"2011","journal-title":"Turk. J. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jsbmb.2017.01.017","article-title":"1,25(OH)(2)D-3 and calcipotriol, its hypocalcemic analog, exert a long-lasting anti-inflammatory and anti-proliferative effect in synoviocytes cultured from patients with rheumatoid arthritis and osteoarthritis","volume":"173","author":"Huhtakangas","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Qian, Y., Zhong, P., Liang, D., Xu, Z., Skibba, M., Zeng, C., Li, X., Wei, T., Wu, L., and Liang, G. (2015). A newly designed curcumin analog Y20 mitigates cardiac injury via anti-inflammatory and anti-oxidant actions in obese rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120215"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.4048\/jbc.2015.18.3.225","article-title":"Cellular Effect of Curcumin and Citral Combination on Breast Cancer Cells: Induction of Apoptosis and Cell Cycle Arrest","volume":"18","author":"Patel","year":"2015","journal-title":"J. Breast Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1016\/j.metabol.2008.06.014","article-title":"Beneficial effects of curcumin on hyperlipidemia and insulin resistance in high-fat-fed hamsters","volume":"57","author":"Jang","year":"2008","journal-title":"Metabolism"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Deligiannidou, G.-E., Papadopoulos, R.-E., Kontogiorgis, C., Detsi, A., Bezirtzoglou, E., and Constantinides, T. (2020). Unraveling Natural Products\u2019 Role in Osteoarthritis Management\u2014An Overview. Antioxidants, 9.","DOI":"10.3390\/antiox9040348"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Calabrese, G., Zappal\u00e0, A., Dolcimascolo, A., Acquaviva, R., Parenti, R., and Malfa, G.A. (2021). Phytochemical Analysis and Anti-Inflammatory and Anti-Osteoarthritic Bioactive Potential of Verbascum thapsus L. (Scrophulariaceae) Leaf Extract Evaluated in Two In Vitro Models of Inflammation and Osteoarthritis. Molecules, 26.","DOI":"10.3390\/molecules26175392"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1007\/s11655-010-0512-2","article-title":"Progress on integrated Chinese and Western medicine in the treatment of osteoarthritis","volume":"16","author":"Wang","year":"2010","journal-title":"Chin. J. Integr. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.bcp.2007.08.016","article-title":"Curcumin as \u201cCurecumin\u201d: From kitchen to clinic","volume":"75","author":"Goel","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s12035-014-9021-1","article-title":"Strategy to Suppress Oxidative Damage-Induced Neurotoxicity in PC12 Cells by Curcumin: The Role of ROS-Mediated DNA Damage and the MAPK and AKT Pathways","volume":"53","author":"Fu","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"28556","DOI":"10.1074\/jbc.M111.256180","article-title":"Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: Role of the phosphatidylinositol 3-kinase\/Akt pathway","volume":"286","author":"Buhrmann","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/ddr.21509","article-title":"Curcumin reduces inflammation in knee osteoarthritis rats through blocking TLR4\/MyD88\/NF-\u03baB signal pathway","volume":"80","author":"Zhang","year":"2019","journal-title":"Drug Dev. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chiarelli, R., Caradonna, F., and Naselli, F. (2024). Autophagy and nutrigenomics: A winning team against chronic disease and tumors. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1409142"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.2147\/IJN.S82788","article-title":"Curcumin-loaded colloidal carrier system: Formulation optimization, mechanistic insight, ex vivo and in vivo evaluation","volume":"10","author":"Naz","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_41","unstructured":"Bruce, M.R. (2012). Biochemical Mediators Involved in Cartilage Degradation and the Induction of Pain in Osteoarthritis. Principles of Osteoarthritis, IntechOpen."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Naselli, F., Bellavia, D., Costa, V., De Luca, A., Raimondi, L., Giavaresi, G., and Caradonna, F. (2024). Osteoarthritis in the Elderly Population: Preclinical Evidence of Nutrigenomic Activities of Flavonoids. Nutrients, 16.","DOI":"10.3390\/nu16010112"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1590\/S0102-86502014001800006","article-title":"Oral administration of curcumin (Curcuma longa) can attenuate the neutrophil inflammatory response in zymosan-induced arthritis in rats","volume":"29","author":"Nonose","year":"2014","journal-title":"Acta Cir. Bras."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Chen, I.-J., and Wong, C.-S. (2020). Shea Nut Oil Extracts Enhance the Intra-Articular Sodium Hyaluronate Effectiveness on Surgically Induced OA Progression in Rats. Nutrients, 12.","DOI":"10.3390\/nu12040957"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Huang, N.-C., Yang, T.-S., Busa, P., Lin, C.-L., Fang, Y.-C., Chen, I.-J., and Wong, C.-S. (2021). Detection and Evaluation of Serological Biomarkers to Predict Osteoarthritis in Anterior Cruciate Ligament Transection Combined Medial Meniscectomy Rat Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910179"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Busa, P., Lee, S.-O., Huang, N., Kuthati, Y., and Wong, C.-S. (2022). Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2\/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study. Antioxidants, 11.","DOI":"10.3390\/antiox11061209"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e15268","DOI":"10.1016\/j.heliyon.2023.e15268","article-title":"Vitamin D reduces pain and cartilage destruction in knee osteoarthritis animals through inhibiting the matrix metalloprotease (MMPs) expression","volume":"9","author":"Busa","year":"2023","journal-title":"Heliyon"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8799","DOI":"10.3892\/mmr.2017.7762","article-title":"The association between parathyroid hormone 1-34 and the Wnt\/beta-catenin signaling pathway in a rat model of osteoarthritis","volume":"16","author":"Ma","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Sudirman, S., Ong, A.D., Chang, H.W., and Kong, Z.L. (2018). Effect of Fucoidan on Anterior Cruciate Ligament Transection and Medial Meniscectomy Induced Osteoarthritis in High-Fat Diet-Induced Obese Rats. Nutrients, 10.","DOI":"10.20944\/preprints201805.0053.v1"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.3346\/jkms.2014.29.8.1042","article-title":"Withaferin A-Caused Production of Intracellular Reactive Oxygen Species Modulates Apoptosis via PI3K\/Akt and JNKinase in Rabbit Articular Chondrocytes","volume":"29","author":"Yu","year":"2014","journal-title":"J. Korean Med. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/biof.5520130104","article-title":"Dietary docosahexaenoic acid does not promote tissue lipid peroxide formation to the extent expected from the peroxidizability index of the lipids","volume":"13","author":"Saito","year":"2000","journal-title":"BioFactors"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.bbadis.2016.01.003","article-title":"ROS\/oxidative stress signaling in osteoarthritis","volume":"1862","author":"Lepetsos","year":"2016","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.joca.2007.09.012","article-title":"Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis","volume":"16","author":"Davies","year":"2008","journal-title":"Osteoarthr. Cartil."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/2\/349\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:31:46Z","timestamp":1759919506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/2\/349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,19]]},"references-count":53,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["nu17020349"],"URL":"https:\/\/doi.org\/10.3390\/nu17020349","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,19]]}}}