{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:23:13Z","timestamp":1791919393895,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,9,2]],"date-time":"2023-09-02T00:00:00Z","timestamp":1693612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013769","name":"Orthopaedic Trauma Association","doi-asserted-by":"publisher","award":["2819"],"award-info":[{"award-number":["2819"]}],"id":[{"id":"10.13039\/100013769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013769","name":"Orthopaedic Trauma Association","doi-asserted-by":"publisher","award":["W81XWH1910201"],"award-info":[{"award-number":["W81XWH1910201"]}],"id":[{"id":"10.13039\/100013769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Army Medical Research and Development Command","doi-asserted-by":"publisher","award":["2819"],"award-info":[{"award-number":["2819"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Army Medical Research and Development Command","doi-asserted-by":"publisher","award":["W81XWH1910201"],"award-info":[{"award-number":["W81XWH1910201"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intra-articular fractures (IAF) result in significant and prolonged inflammation, increasing the chances of developing post-traumatic osteoarthritis (PTOA). Interleukin-one beta (IL-1\u03b2) and Tumor Necrosis Factor-alpha (TNF-\u03b1) are key inflammatory factors shown to be involved in osteochondral degradation following IAF. As such, use of targeted biologics such as Infliximab (INX), a TNF-\u03b1 inhibitor, and Anakinra (ANR), an interleukin-one (IL-1) receptor antagonist (IL1RA), may protect against PTOA by damping the inflammatory response to IAF and reducing osteochondral degradation. To test this hypothesis, IAFs were induced in the hindlimb knee joints of rats treated with INX at 10 mg\/kg\/day, ANR at 100 g\/kg\/day, or saline (vehicle control) by subcutaneous infusion for a period of two weeks and healing was evaluated at 8-weeks post injury. Serum and synovial fluid (SF) were analyzed for soluble factors. In-vivo microcomputed tomography (\u00b5CT) scans assessed bone mineral density and bone morphometry measurements. Cationic CA4+ agent assessed articular cartilage composition via ex vivo \u00b5CT. Scoring according to the Osteoarthritis Research Society International (OARSI) guidelines was performed on stained histologic tibia sections at the 56-day endpoint on a 0\u20136 scale. Systemically, ANR reduced many pro-inflammatory cytokines and reduced osteochondral degradation markers Cross Linked C-Telopeptide Of Type II (CTXII, p &lt; 0.05) and tartrate-resistant acid phosphatase (TRAP, p &lt; 0.05). ANR treatment resulted in increased chemokines; macrophage-chemotractant protein-1 (MCP-1), MPC-3, macrophage inhibitory protein 2 (MIP2) with a concomitant decrease in proinflammatory interleukin-17A (IL17A) at 14 days post-injury within the SF. Microcomputed tomography (\u00b5CT) at 56 days post-injury revealed ANR Treatment decreased epiphyseal degree of anisotropy (DA) (p &lt; 0.05) relative to saline. No differences were found with OARSI scoring but contrast-enhanced \u00b5CT revealed a reduction in glycosaminoglycan content with ANR treatment. These findings suggest targeted cytokine inhibition, specifically IL-1 signaling, as a monotherapy has minimal utility for improving IAF healing outcomes but may have utility for promoting a more permissive inflammatory environment that would allow more potent disease modifying osteoarthritis drugs to mitigate the progression of PTOA after IAF.<\/jats:p>","DOI":"10.3390\/ijms241713606","type":"journal-article","created":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T02:14:50Z","timestamp":1693793690000},"page":"13606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Effect of Targeted Cytokine Inhibition on Progression of Post-Traumatic Osteoarthritis Following Intra-Articular Fracture"],"prefix":"10.3390","volume":"24","author":[{"given":"Michael S.","family":"Valerio","sequence":"first","affiliation":[{"name":"Research & Surveillance Division, DoD-VA Extremity Trauma and Amputation Center of Excellence, Bethesda, MD 20814, USA"},{"name":"Department of Surgery, Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge B.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Surgery, Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor P.","family":"Dolan","sequence":"additional","affiliation":[{"name":"Research & Surveillance Division, DoD-VA Extremity Trauma and Amputation Center of Excellence, Bethesda, MD 20814, USA"},{"name":"Department of Surgery, Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-3832","authenticated-orcid":false,"given":"Jessica M.","family":"Motherwell","sequence":"additional","affiliation":[{"name":"Research & Surveillance Division, DoD-VA Extremity Trauma and Amputation Center of Excellence, Bethesda, MD 20814, USA"},{"name":"Department of Surgery, Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin K.","family":"Potter","sequence":"additional","affiliation":[{"name":"Department of Surgery, Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Department of Orthopaedic Surgery, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3701-0950","authenticated-orcid":false,"given":"Christopher L.","family":"Dearth","sequence":"additional","affiliation":[{"name":"Research & Surveillance Division, DoD-VA Extremity Trauma and Amputation Center of Excellence, Bethesda, MD 20814, USA"},{"name":"Department of Surgery, Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2244-1443","authenticated-orcid":false,"given":"Stephen M.","family":"Goldman","sequence":"additional","affiliation":[{"name":"Research & Surveillance Division, DoD-VA Extremity Trauma and Amputation Center of Excellence, Bethesda, MD 20814, USA"},{"name":"Department of Surgery, Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1097\/BOT.0b013e3181ed298d","article-title":"Basic science of intra-articular fractures and posttraumatic osteoarthritis","volume":"24","author":"McKinley","year":"2010","journal-title":"J. Orthop. Trauma"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20","DOI":"10.5435\/JAAOS-22-01-20","article-title":"Pathogenesis and prevention of posttraumatic osteoarthritis after intra-articular fracture","volume":"22","author":"Schenker","year":"2014","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.7326\/0003-4819-133-5-200009050-00007","article-title":"Joint injury in young adults and risk for subsequent knee and hip osteoarthritis","volume":"133","author":"Gelber","year":"2000","journal-title":"Ann. Intern. Med."},{"key":"ref_4","first-page":"21s","article-title":"Osteoarthritis Treatment in the Veteran Population","volume":"32","author":"Stanishewski","year":"2015","journal-title":"Fed. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1097\/01.bot.0000246468.80635.ef","article-title":"Posttraumatic osteoarthritis: A first estimate of incidence, prevalence, and burden of disease","volume":"20","author":"Brown","year":"2006","journal-title":"J. Orthop. Trauma"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/art.20776","article-title":"Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage","volume":"52","author":"Kobayashi","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8897440","DOI":"10.1155\/2021\/8897440","article-title":"Elevation of Inflammatory Cytokines and Proteins after Intra-Articular Ankle Fracture: A Cross-Sectional Study of 47 Ankle Fracture Patients","volume":"2021","author":"Pham","year":"2021","journal-title":"Mediat. Inflamm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e000279","DOI":"10.1136\/rmdopen-2016-000279","article-title":"Post-traumatic arthritis: Overview on pathogenic mechanisms and role of inflammation","volume":"2","author":"Punzi","year":"2016","journal-title":"RMD Open"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Iversen, I.J., Pham, T.M., and Schmal, H. (2021). Do acute inflammatory cytokines affect 3- and 12-month postoperative functional outcomes-a prospective cohort study of 12 patients with proximal tibia fractures. BMC Musculoskelet. Disord., 22.","DOI":"10.1186\/s12891-021-04207-7"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Garcia, K.S., de Azevedo, M.F.C., Carlos, A.S., Barros, L.L., Oba, J., Sobrado Junior, C.W., Sipahi, A.M., Alves, O.D.C., Navarro-Rodriguez, T., and Parra, R.S. (2023). Efficacy of Early Optimization of Infliximab Guided by Therapeutic Drug Monitoring during Induction-A Prospective Trial. Biomedicines, 11.","DOI":"10.3390\/biomedicines11061757"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ku, E.J., Kim, B.R., Lee, J.I., Lee, Y.K., Oh, T.J., Jang, H.C., and Choi, S.H. (2022). The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094906"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1136\/annrheumdis-2012-eular.2761","article-title":"FRI0304\u2005Treatment of knee osteoarthritis with intra-articular infliximab improves total womac score. High baseline levels of synovial cellularity predict improvement","volume":"71","author":"Lindsley","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_13","first-page":"183","article-title":"Infliximab in the treatment of rheumatoid arthritis","volume":"3","author":"Perdriger","year":"2009","journal-title":"Biologics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1002\/art.24800","article-title":"The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting tumor necrosis factor alpha on chondroprotection in an animal model","volume":"60","author":"Elsaid","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1002\/art.24513","article-title":"Efficacy of intraarticular infliximab in patients with chronic or recurrent gonarthritis: A clinical randomized trial","volume":"61","author":"Teng","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s10753-010-9259-3","article-title":"Protective effects of indomethacin and cyclophosphamide but not of infliximab on liver metabolic changes caused by adjuvant-induced arthritis","volume":"34","author":"Bracht","year":"2011","journal-title":"Inflammation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.3899\/jrheum.090074","article-title":"Anakinra for rheumatoid arthritis: A systematic review","volume":"36","author":"Mertens","year":"2009","journal-title":"J. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11926-007-0019-9","article-title":"Treatment of osteoarthritis with anakinra","volume":"9","author":"Iqbal","year":"2007","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R134","DOI":"10.1186\/ar4591","article-title":"Targeting pro-inflammatory cytokines following joint injury: Acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis","volume":"16","author":"Furman","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"124","DOI":"10.22203\/eCM.v029a10","article-title":"Sustained intra-articular delivery of IL-1RA from a thermally-responsive elastin-like polypeptide as a therapy for post-traumatic arthritis","volume":"29","author":"Kimmerling","year":"2015","journal-title":"Eur. Cell Mater."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fphar.2017.00282","article-title":"Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin-1alpha and -1beta, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis","volume":"8","author":"Nasi","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9356","DOI":"10.3390\/ijms24119356","article-title":"The Potential of MSC-Based Cell-Free Therapy in Wound Healing&mdash;A Thorough Literature Review","volume":"24","author":"Ma","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"386","DOI":"10.3389\/fendo.2020.00386","article-title":"Modulation of the Inflammatory Response and Bone Healing","volume":"11","author":"Maruyama","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s40264-015-0366-9","article-title":"Hepatotoxicity Associated with the Use of Anti-TNF-alpha Agents","volume":"39","author":"French","year":"2016","journal-title":"Drug Saf."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"437","DOI":"10.4103\/wjnm.WJNM_84_18","article-title":"Infliximab-induced hot kidneys on bone scintigraphy","volume":"18","author":"Cayir","year":"2019","journal-title":"World J. Nucl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1742-481X.2012.00950.x","article-title":"Effects of immunosuppressive therapy on wound healing","volume":"10","author":"Bootun","year":"2013","journal-title":"Int. Wound J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ishikawa, M., Ito, H., Kitaori, T., Murata, K., Shibuya, H., Furu, M., Yoshitomi, H., Fujii, T., Yamamoto, K., and Matsuda, S. (2014). MCP\/CCR2 signaling is essential for recruitment of mesenchymal progenitor cells during the early phase of fracture healing. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104954"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.imlet.2013.05.012","article-title":"Cytokine productive capacity of alveolar macrophages and Kupffer cells after femoral fracture and blunt chest trauma in a murine trauma model","volume":"152","author":"Neunaber","year":"2013","journal-title":"Immunol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3389\/fendo.2017.00039","article-title":"Potential Role of Chemokines in Fracture Repair","volume":"8","author":"Edderkaoui","year":"2017","journal-title":"Front. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1084\/jem.20160393","article-title":"G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling","volume":"213","author":"Bajrami","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.4049\/jimmunol.1701502","article-title":"IL-2-Anti-IL-2 Monoclonal Antibody Immune Complexes Inhibit Collagen-Induced Arthritis by Augmenting Regulatory T Cell Functions","volume":"201","author":"Yokoyama","year":"2018","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5493","DOI":"10.1172\/JCI134091","article-title":"IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis","volume":"130","author":"Faust","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1177\/1759720X13485328","article-title":"Targeting interleukin-17 in patients with active rheumatoid arthritis: Rationale and clinical potential","volume":"5","author":"Kellner","year":"2013","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/jor.22940","article-title":"Therapeutic opportunities to prevent post-traumatic arthritis: Lessons from the natural history of arthritis after articular fracture","volume":"33","author":"Olson","year":"2015","journal-title":"J. Orthop. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.4049\/jimmunol.0803007","article-title":"The mechanism of osteoclast differentiation induced by IL-1","volume":"183","author":"Kim","year":"2009","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1172\/JCI200523394","article-title":"IL-1 mediates TNF-induced osteoclastogenesis","volume":"115","author":"Wei","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1053\/joca.2002.0821","article-title":"A comparative analysis of bone and cartilage metabolism in two strains of guinea-pig with varying degrees of naturally occurring osteoarthritis","volume":"10","author":"Huebner","year":"2002","journal-title":"Osteoarthr. Cartil."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1097\/BOT.0000000000001063","article-title":"Fracture and Dislocation Classification Compendium-2018","volume":"32","author":"Meinberg","year":"2018","journal-title":"J. Orthop. Trauma"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.joca.2007.03.017","article-title":"Measurement of synovial fluid volume using urea","volume":"15","author":"Kraus","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Rieppo, L., Janssen, L., Rahunen, K., Lehenkari, P., Finnila, M.A.J., and Saarakkala, S. (2019). Histochemical quantification of collagen content in articular cartilage. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224839"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13606\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:45:31Z","timestamp":1760129131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13606"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,2]]},"references-count":40,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713606"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713606","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,2]]}}}