{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:45:48Z","timestamp":1785415548400,"version":"3.56.0"},"reference-count":46,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"crossref","award":["KOITA-2026-0002-03"],"award-info":[{"award-number":["KOITA-2026-0002-03"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"crossref"}]},{"award":["KOITA-2026-0002-03"],"award-info":[{"award-number":["KOITA-2026-0002-03"]}],"id":[{"id":"https:\/\/ror.org\/01wpjm123","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministry of Education (MOE) and the Gyeongsangbuk-do, Republic of Korea","award":["2026-RISE-15-118"],"award-info":[{"award-number":["2026-RISE-15-118"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) remains an alarming therapeutic challenge, as conventional intra-articular interventions primarily address symptomatic relief without halting progressive cartilage and bone degeneration. In this study, we investigated the disease-modifying potential of Cyclo(His-Pro) (CHP) in a monosodium iodoacetate (MIA)-induced OA rat model. Intra-articular CHP yielded significant clinical improvements, reducing joint edema and reversing OA-induced mechanical and thermal hypersensitivity, as evidenced by lifting behavior, rotarod performance, and hot plate tests. Beyond analgesia, micro-computed tomography (micro-CT) analysis showed that CHP preserved subchondral bone architecture, restoring trabecular volume and thickness and reducing serum C-terminal telopeptide of type II collagen (CTX-2), indicative of suppressed cartilage degradation. At the molecular level, CHP reprogrammed the joint microenvironment by suppressing Cox2, Adamts5, Mmp13, Mmp1, Mmp2, and Timp2 expression and decreasing systemic prostaglandin E2 (PGE2) levels. Moreover, CHP showed efficacy comparable to Conjuran, a polynucleotide-based mechanical supportive agent, while additionally targeting COX-2\/PGE2-driven inflammatory cascades and cartilage catabolic pathways. Collectively, these findings indicate that intra-articular CHP confers combined analgesic, chondroprotective, and osteoprotective effects, supporting its potential as a promising disease-modifying osteoarthritis drug candidate.<\/jats:p>","DOI":"10.3390\/ijms27114742","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T11:57:44Z","timestamp":1779710264000},"page":"4742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intra-Articular Cyclo(His-Pro) Attenuates Monosodium Iodoacetate-Induced Osteoarthritis by Suppressing COX-2\/PGE2 Signaling and Cartilage Catabolism in Rats"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4760-018X","authenticated-orcid":false,"given":"Gyuwon","family":"Huh","sequence":"first","affiliation":[{"name":"R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0005-6886","authenticated-orcid":false,"given":"Dohyun","family":"Lee","sequence":"additional","affiliation":[{"name":"R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1699-0067","authenticated-orcid":false,"given":"Jongsu","family":"Jeon","sequence":"additional","affiliation":[{"name":"R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1158-5647","authenticated-orcid":false,"given":"Daehun","family":"Kim","sequence":"additional","affiliation":[{"name":"R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea"},{"name":"Division of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoe-Yune","family":"Jung","sequence":"additional","affiliation":[{"name":"R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea"},{"name":"Division of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Osteoarthritis Collaborators (2023). Global, regional, and national burden of osteoarthritis, 1990\u20132020 and projections to 2050: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol., 5, e508\u2013e522."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16072","DOI":"10.1038\/nrdp.2016.72","article-title":"Osteoarthritis","volume":"2","author":"Barr","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_4","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_5","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_6","doi-asserted-by":"crossref","first-page":"e46612","DOI":"10.1097\/MD.0000000000046612","article-title":"Osteoarthritis burden across 204 countries and territories during 1990 to 2021: Insights from the Global Burden of Disease Study 2021","volume":"104","author":"Zeng","year":"2025","journal-title":"Medicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.1007\/s10067-025-07740-1","article-title":"The escalating burden of osteoarthritis in East and Southeast Asia: An information-analytical study from the GBD 2021","volume":"44","author":"Zhou","year":"2025","journal-title":"Clin. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7907","DOI":"10.1038\/s41598-025-91783-6","article-title":"Global, regional, and national epidemiology of osteoarthritis in working-age individuals: Insights from the global burden of disease study 1990\u20132021","volume":"15","author":"Ma","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19528","DOI":"10.1038\/s41598-023-46279-6","article-title":"National trends in rheumatoid arthritis and osteoarthritis prevalence in South Korea, 1998\u20132021","volume":"13","author":"Park","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/s41584-018-0073-x","article-title":"Modern-day environmental factors in the pathogenesis of osteoarthritis","volume":"14","author":"Berenbaum","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"821","DOI":"10.18433\/J3VW2F","article-title":"Adverse effects of nonsteroidal antiinflammatory drugs: An update of gastrointestinal, cardiovascular and renal complications","volume":"16","author":"Harirforoosh","year":"2013","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1016\/j.joca.2021.08.010","article-title":"Are topical non-steroidal anti-inflammatory drugs (NSAIDs) safer than oral NSAIDs? Or are the adverse effects of topical NSAIDs comparable to those of oral NSAIDs?","volume":"29","author":"Toda","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Han, H., Ro, D.H., Han, H.S., and Won, S. (2025). Overall compilation of adverse effects of non-steroidal anti-inflammatory drugs: A hypothesis-free systematic investigation using a nationwide cohort study. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1539328"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e70428","DOI":"10.1002\/jeo2.70428","article-title":"The promising potential of polynucleotide injections for knee osteoarthritis: A systematic review of literature and meta-analysis of randomized control trials","volume":"12","author":"Elphingstone","year":"2025","journal-title":"J. Exp. Orthop."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Farinelli, L., Riccio, M., Gigante, A., and De Francesco, F. (2024). Pain Management Strategies in Osteoarthritis. Biomedicines, 12.","DOI":"10.3390\/biomedicines12040805"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Testa, G., Giardina, S.M.C., Culmone, A., Vescio, A., Turchetta, M., Cannavo, S., and Pavone, V. (2021). Intra-Articular Injections in Knee Osteoarthritis: A Review of Literature. J. Funct. Morphol. Kinesiol., 6.","DOI":"10.3390\/jfmk6010015"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.mcn.2018.11.002","article-title":"Cyclo(His-Pro) inhibits NLRP3 inflammasome cascade in ALS microglial cells","volume":"94","author":"Grottelli","year":"2019","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"115776","DOI":"10.1016\/j.biopha.2023.115776","article-title":"Inhibition of chloride intracellular channel protein 1 (CLIC1) ameliorates liver fibrosis phenotype by activating the Ca(2+)-dependent Nrf2 pathway","volume":"168","author":"Ko","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lee, D., Jeon, J., Baek, S., Park, O., Kim, A.R., Do, M.S., and Jung, H.Y. (2024). CycloZ Suppresses TLR4-Driven Inflammation to Reduce Asthma-Like Responses in HDM-Exposed Mouse Models. Cells, 13.","DOI":"10.3390\/cells13232034"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Grottelli, S., Ferrari, I., Pietrini, G., Peirce, M.J., Minelli, A., and Bellezza, I. (2016). The Role of Cyclo(His-Pro) in Neurodegeneration. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17081332"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Won, M.H., and Shin, S.H. (2026). Development and validation of the sedentary behavior regulation scale in Korean Adults Population. PLoS ONE, 21.","DOI":"10.1371\/journal.pone.0346963"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100815","DOI":"10.1016\/j.jhepr.2023.100815","article-title":"Cyclo(His-Pro): A further step in the management of steatohepatitis","volume":"5","author":"Li","year":"2023","journal-title":"JHEP Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2305927","DOI":"10.1002\/advs.202305927","article-title":"Cyclo His-Pro Attenuates Muscle Degeneration in Murine Myopathy Models","volume":"11","author":"Zanou","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e23819","DOI":"10.1096\/fj.202400854R","article-title":"Protective effect of Cyclo(His-Pro) on peritoneal fibrosis through regulation of HDAC3 expression","volume":"38","author":"Kim","year":"2024","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7842","DOI":"10.1039\/D0FO00992J","article-title":"Cissus quadrangularis (veldt grape) attenuates disease progression and anatomical changes in mono sodium iodoacetate (MIA)-induced knee osteoarthritis in the rat model","volume":"11","author":"Lakshmanan","year":"2020","journal-title":"Food Funct."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Morais, S.V., Mendonca, P.G., Vasconcelos, C.C., Lopes, P.L.A., Garcia, J.B.S., Calzerra, N.T.M., Queiroz, T.M., Lima, S., Silva, G.E.B., and Lopes, A.J.O. (2023). Cuminaldehyde Effects in a MIA-Induced Experimental Model Osteoarthritis in Rat Knees. Metabolites, 13.","DOI":"10.3390\/metabo13030397"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1186\/s12967-022-03515-3","article-title":"Soluble CCR2 gene therapy controls joint inflammation, cartilage damage, and the progression of osteoarthritis by targeting MCP-1 in a monosodium iodoacetate (MIA)-induced OA rat model","volume":"20","author":"Na","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"South, S.M., Crabtree, K., Averitt, D.L., Vijayagopal, P., and Juma, S. (2025). Anti-Inflammatory and Joint-Protective Effects of Blueberries in a Monosodium Iodoacetate (MIA)-Induced Rat Model of Osteoarthritis. Nutrients, 17.","DOI":"10.3390\/nu17132134"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1177\/03635465231212668","article-title":"The Combined Intraosseous Administration of Orthobiologics Outperformed Isolated Intra-articular Injections in Alleviating Pain and Cartilage Degeneration in a Rat Model of MIA-Induced Knee Osteoarthritis","volume":"52","author":"Zhang","year":"2024","journal-title":"Am. J. Sports Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117687","DOI":"10.1016\/j.bone.2025.117687","article-title":"Revealing early subchondral bone structural changes in osteoarthritis progression in a collagenase-induced mouse model using microCT","volume":"202","author":"Liu","year":"2026","journal-title":"Bone"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/jor.22250","article-title":"Monosodium iodoacetate induces apoptosis via the mitochondrial pathway involving ROS production and caspase activation in rat chondrocytes in vitro","volume":"31","author":"Jiang","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"156141","DOI":"10.1016\/j.phymed.2024.156141","article-title":"Cannabiorcol as a novel inhibitor of the p38\/MSK-1\/NF-kappaB signaling pathway, reducing matrix metalloproteinases in osteoarthritis","volume":"135","author":"Jeon","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.4049\/jimmunol.181.7.5082","article-title":"Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: Evidence for signaling via the EP4 receptor","volume":"181","author":"Attur","year":"2008","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41413-022-00201-4","article-title":"PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis","volume":"10","author":"Jiang","year":"2022","journal-title":"Bone Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.joca.2008.09.003","article-title":"PGE2 signal via EP2 receptors evoked by a selective agonist enhances regeneration of injured articular cartilage","volume":"17","author":"Otsuka","year":"2009","journal-title":"Osteoarthr. Cartil."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1126\/science.adx6649","article-title":"Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration","volume":"391","author":"Singla","year":"2026","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bryk, M., Chwastek, J., Mlost, J., Kostrzewa, M., and Starowicz, K. (2021). Sodium Monoiodoacetate Dose-Dependent Changes in Matrix Metalloproteinases and Inflammatory Components as Prognostic Factors for the Progression of Osteoarthritis. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.643605"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3109\/13813455.2012.755548","article-title":"TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure","volume":"119","author":"Givvimani","year":"2013","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19476035221115541","DOI":"10.1177\/19476035221115541","article-title":"Evaluation of the Anti-Inflammatory and Chondroprotective Effect of Celecoxib on Cartilage Ex Vivo and in a Rat Osteoarthritis Model","volume":"13","author":"Haartmans","year":"2022","journal-title":"Cartilage"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"116501","DOI":"10.1016\/j.biopha.2024.116501","article-title":"TMF inhibits extracellular matrix degradation by regulating the C\/EBPbeta\/ADAMTS5 signaling pathway in osteoarthritis","volume":"174","author":"Wang","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.joca.2023.04.001","article-title":"Evaluation of S201086\/GLPG1972, an ADAMTS-5 inhibitor, for the treatment of knee osteoarthritis in ROCCELLA: A phase 2 randomized clinical trial","volume":"31","author":"Schnitzer","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jiang, L., Lin, J., Zhao, S., Wu, J., Jin, Y., Yu, L., Wu, N., Wu, Z., Wang, Y., and Lin, M. (2021). ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.703110"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100379","DOI":"10.1016\/j.ocarto.2023.100379","article-title":"Pathological tissue formation and degradation biomarkers correlate with patient reported pain outcomes: An explorative study","volume":"5","author":"Attur","year":"2023","journal-title":"Osteoarthr. Cart. Open"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.joca.2014.05.023","article-title":"Bone-cartilage interface crosstalk in osteoarthritis: Potential pathways and future therapeutic strategies","volume":"22","author":"Yuan","year":"2014","journal-title":"Osteoarthr. Cartil."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/2157-7609.1000105","article-title":"Metabolism and toxicity of high doses of cyclo (His-Pro) plus zinc in healthy human subjects","volume":"1","author":"Uyemura","year":"2010","journal-title":"J. Drug Metab. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"41","DOI":"10.2147\/JPR.S154038","article-title":"Traumatic osteoarthritis-induced persistent mechanical hyperalgesia in a rat model of anterior cruciate ligament transection plus a medial meniscectomy","volume":"11","author":"Tsai","year":"2018","journal-title":"J. Pain Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4742\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T04:23:42Z","timestamp":1779855822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,25]]},"references-count":46,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114742"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114742","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,25]]}}}