Intra-articular delivery of an indoleamine 2,3-dioxygenase galectin-3 fusion protein for osteoarthritis treatment in male Lewis rats

Arthritis Research & Therapy

Research

Benjamin G. Keselowsky¹  Evelyn Bracho-Sanchez¹  Brittany D. Partain¹  Shaheen A. Farhadi¹  Elena G. Yarmola¹  Gregory A. Hudalla¹  Kyle D. Allen² 

[1] J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Biomedical Sciences Building, 32610, Gainesville, FL, USA;J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Biomedical Sciences Building, 32610, Gainesville, FL, USA;Department of Orthopaedic Surgery and Sports Medicine, University of Florida, Gainesville, FL, USA;

关键词: Knee osteoarthritis;    Indoleamine 2,3-dioxygenase;    Galectin-3;    Metabolic reprogramming;    Intra-articular drug delivery;    Inflammation;    Pain and disability;   

DOI  :  10.1186/s13075-023-03153-0

 received in 2023-03-29, accepted in 2023-08-27,  发布年份 2023

来源: Springer

【 摘 要 】

ObjectiveOsteoarthritis (OA) is driven by low-grade inflammation, and controlling local inflammation may offer symptomatic relief. Here, we developed an indoleamine 2,3-dioxygenase and galectin-3 fusion protein (IDO-Gal3), where IDO increases the production of local anti-inflammatory metabolites and Gal3 binds carbohydrates to extend IDO’s joint residence time. In this study, we evaluated IDO-Gal3’s ability to alter OA-associated inflammation and pain-related behaviors in a rat model of established knee OA.MethodsJoint residence was first evaluated with an analog Gal3 fusion protein (NanoLuc™ and Gal3, NL-Gal3) that produces luminescence from furimazine. OA was induced in male Lewis rats via a medial collateral ligament and medial meniscus transection (MCLT + MMT). At 8 weeks, NL or NL-Gal3 were injected intra-articularly (n = 8 per group), and bioluminescence was tracked for 4 weeks. Next, IDO-Gal3s’s ability to modulate OA pain and inflammation was assessed. Again, OA was induced via MCLT + MMT in male Lewis rats, with IDO-Gal3 or saline injected into OA-affected knees at 8 weeks post-surgery (n = 7 per group). Gait and tactile sensitivity were then assessed weekly. At 12 weeks, intra-articular levels of IL6, CCL2, and CTXII were assessed.ResultsThe Gal3 fusion increased joint residence in OA and contralateral knees (p < 0.0001). In OA-affected animals, both saline and IDO-Gal3 improved tactile sensitivity (p = 0.008), but IDO-Gal3 also increased walking velocities (p ≤ 0.033) and improved vertical ground reaction forces (p ≤ 0.04). Finally, IDO-Gal3 decreased intra-articular IL6 levels within the OA-affected joint (p = 0.0025).ConclusionIntra-articular IDO-Gal3 delivery provided long-term modulation of joint inflammation and pain-related behaviors in rats with established OA.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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