Development of a sheep model of knee osteoarthritis and preliminary magnetic resonance–guided focused ultrasound evaluation

Abstract

Knee osteoarthritis (KOA) is a prevalent and disabling disease with limited nonsurgical options for pain management. Magnetic resonance–guided focused ultrasound (MRgFUS) is a noninvasive technique for targeted thermal ablation and has emerged as a potential therapy for pain control. Large-animal models that better replicate human joint anatomy are needed for translational evaluation. Although monosodium iodoacetate (MIA) is widely used to induce KOA in small animals, its application in sheep remains limited. KOA was induced in the right knees of nine sheep using intra-articular MIA injections on days 8 and 29, with contralateral knees serving as controls. Animals were monitored for 12 weeks with serial behavioral and radiographic assessments. MRgFUS treatment was performed between weeks 6 and 8 after the first MIA injection. At the study endpoint, knee joints were obtained for macroscopic and histological evaluation. MIA-treated knees demonstrated radiographic features of KOA, including joint space narrowing and osteophyte formation. Gross and histological analyses confirmed cartilage degeneration, with surface erosion, reduced proteoglycan staining, and disrupted cartilage architecture. Despite consistent structural changes, only two animals developed persistent pain-related behaviors. In these animals, MRgFUS treatment was associated with improved pain scores and activity levels. No treatment-related increases in pain, functional impairment, or tissue damage were observed. Intra-articular MIA injection produced a reproducible structural model of KOA in sheep. MRgFUS was well tolerated and exhibited preliminary potential for pain relief, supporting further evaluation in larger controlled studies.

Keywords

magnetic resonance imaging / magnetic Resonance-Guided Focused Ultrasound / osteoarthritis / sheep model

References

[1] Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012; 64(6): 1697-1707.

[2] Collaborators, G.B.D.O. Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023; 5(9): e508-e522.

[3] Fallon EA, Boring MA, Foster AL, et al. Prevalence of diagnosed arthritis—United States, 2019–2021. MMWR Morb Mortal Wkly Rep. 2023; 2023(72): 1101-1107.

[4] Long H, Liu Q, Yin H, et al. Prevalence trends of site-specific osteoarthritis from 1990 to 2019: findings from the Global Burden of Disease Study 2019. Arthritis Rheumatol. 2022; 74(7): 1172-1183.

[5] Gelber AC. Knee osteoarthritis. Ann Intern Med. 2024; 177(9): ITC129-ITC144.

[6] Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the Management of Osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2020; 72(2): 149-162.

[7] Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem Pharmacol. 2020; 180:114147.

[8] Samuels J, Pillinger MH, Jevsevar D, Felson D, Simon LS. Critical appraisal of intra-articular glucocorticoid injections for symptomatic osteoarthritis of the knee. Osteoarthr Cartil. 2021; 29(1): 8-16.

[9] Evans JT, Walker RW, Evans JP, Blom AW, Sayers A, Whitehouse MR. How long does a knee replacement last? A systematic review and meta-analysis of case series and national registry reports with more than 15 years of follow-up. Lancet. 2019; 393(10172): 655-663.

[10] McCoy AM. Animal models of osteoarthritis: comparisons and key considerations. Vet Pathol. 2015; 52(5): 803-818.

[11] Song X, Liu Y, Chen S, et al. Knee osteoarthritis: a review of animal models and intervention of traditional Chinese medicine. Animal Model Exp Med. 2024; 7(2): 114-126.

[12] Poole R, Blake S, Buschmann M, et al. Recommendations for the use of preclinical models in the study and treatment of osteoarthritis. Osteoarthr Cartil. 2010; 18(Suppl 3): S10-S16.

[13] Bove SE, Calcaterra SL, Brooker RM, et al. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Osteoarthr Cartil. 2003; 11(11): 821-830.

[14] Pitcher T, Sousa-Valente J, Malcangio M. The monoiodoacetate model of osteoarthritis pain in the mouse. J Vis Exp. 2016; 2016(111):53746.

[15] Lampropoulou-Adamidou K, Lelovas P, Karadimas EV, et al. Useful animal models for the research of osteoarthritis. Eur J Orthop Surg Traumatol. 2014; 24(3): 263-271.

[16] Little CB, Smith MM, Cake MA, Read RA, Murphy MJ, Barry FP. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in sheep and goats. Osteoarthr Cartil. 2010; 18(Suppl 3): S80-S92.

[17] Proffen BL, McElfresh M, Fleming BC, Murray MM. A comparative anatomical study of the human knee and six animal species. Knee. 2012; 19(4): 493-499.

[18] Bazzocchi A, Napoli A, Sacconi B, et al. MRI-guided focused ultrasound surgery in musculoskeletal diseases: the hot topics. Br J Radiol. 2016; 89(1057):20150358.

[19] Grogan DP, Abduhalikov T, Kassell NF, Moosa S. Future directions of MR-guided focused ultrasound. Magn Reson Imaging Clin N Am. 2024; 32(4): 705-715.

[20] Ghanouni P, Krishna V, Eisenberg HM, et al. Unilateral magnetic resonance-guided focused ultrasound for medication-refractory essential tremor: 5-year continued access study. Front Neurol. 2025; 16:1659203.

[21] Cobianchi Bellisari F, Palumbo P, Masciocchi C, Zoccali C, Barile A, Arrigoni F. Needleless ablation of osteoid osteoma and osteoblastoma: the emergent role of MRgFUS. J Clin Med. 2021; 11(1):128.

[22] Jeanmonod D, Werner B, Morel A, et al. Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurg Focus. 2012; 32(1): E1.

[23] Jung HH, Kim SJ, Roh D, et al. Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study. Mol Psychiatry. 2015; 20(10): 1205-1211.

[24] Gofeld M, Smith KJ, Bhatia A, et al. Fluoroscopy-guided high-intensity focused ultrasound neurotomy of the lumbar zygapophyseal joints: a prospective, open-label study. Reg Anesth Pain Med. 2025; 50(6): 464-470.

[25] Izumi M, Ikeuchi M, Kawasaki M, et al. MR-guided focused ultrasound for the novel and innovative management of osteoarthritic knee pain. BMC Musculoskelet Disord. 2013; 14: 267.

[26] Kawasaki M, Muramatsu S, Namba H, et al. Efficacy and safety of magnetic resonance-guided focused ultrasound treatment for refractory chronic pain of medial knee osteoarthritis. Int J Hyperth. 2021; 38(2): 46-55.

[27] Tiegs-Heiden CA, Long Z, Lu A, Gorny KR, Hesley GK. Osteoarthritis-related knee pain: MRI-guided focused ultrasound ablation treatment. Int J Hyperth. 2025; 42(1):2451686.

[28] Weeks EM, Platt MW, Gedroyc W. MRI-guided focused ultrasound (MRgFUS) to treat facet joint osteoarthritis low back pain—case series of an innovative new technique. Eur Radiol. 2012; 22(12): 2822-2835.

[29] Guingamp C, Gegout-Pottie P, Philippe L, Terlain B, Netter P, Gillet P. Mono-iodoacetate-induced experimental osteoarthritis: a dose-response study of loss of mobility, morphology, and biochemistry. Arthritis Rheum. 1997; 40(9): 1670-1679.

[30] Sukerkar PA, Doyle Z. Imaging of osteoarthritis of the knee. Radiol Clin North Am. 2022; 60(4): 605-616.

[31] Schmitz N, Laverty S, Kraus VB, Aigner T. Basic methods in histopathology of joint tissues. Osteoarthr Cartil. 2010; 18(Suppl 3): S113-S116.

[32] Veronesi F, Vandenbulcke F, Ashmore K, et al. Meniscectomy-induced osteoarthritis in the sheep model for the investigation of therapeutic strategies: a systematic review. Int Orthop. 2020; 44(4): 779-793.

[33] Anderson DD, Chubinskaya S, Guilak F, et al. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res. 2011; 29(6): 802-809.

[34] Gregory MH, Capito N, Kuroki K, Stoker AM, Cook JL, Sherman SL. A review of translational animal models for knee osteoarthritis. Arthritis. 2012; 2012:764621.

[35] Ogbonna AC, Clark AK, Gentry C, Hobbs C, Malcangio M. Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice. Eur J Pain. 2013; 17(4): 514-526.

[36] Hannon CP, Goodman SM, Austin MS, et al. 2023 American College of Rheumatology and American Association of Hip and Knee Surgeons clinical practice guideline for the optimal timing of elective hip or knee arthroplasty for patients with symptomatic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy is ineffective. Arthritis Rheumatol. 2023; 75(11): 1877-1888.

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2026 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.