J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Biomedical Sciences Building, Gainesville, FL, 32610, USA.
Department of Orthopaedic Surgery and Sports Medicine, University of Florida, Gainesville, FL, USA.
Arthritis Res Ther. 2023 Sep 18;25(1):173. doi: 10.1186/s13075-023-03153-0.
Osteoarthritis (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.
Joint 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.
The 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).
Intra-articular IDO-Gal3 delivery provided long-term modulation of joint inflammation and pain-related behaviors in rats with established OA.
骨关节炎（OA）是由低水平炎症驱动的，控制局部炎症可能会提供症状缓解。在这里，我们开发了一种色氨酸 2,3-双加氧酶和半乳糖凝集素-3 融合蛋白（IDO-Gal3），其中 IDO 增加局部抗炎代谢物的产生，Gal3 结合碳水化合物以延长 IDO 的关节停留时间。在这项研究中，我们评估了 IDO-Gal3 在建立的膝骨关节炎大鼠模型中改变 OA 相关炎症和疼痛相关行为的能力。
首先使用类似的 Gal3 融合蛋白（NanoLuc™和 Gal3，NL-Gal3）评估关节停留情况，该融合蛋白从 furimazine 产生发光。通过内侧副韧带和内侧半月板切断术（MCLT+MMT）在雄性 Lewis 大鼠中诱导 OA。在 8 周时，NL 或 NL-Gal3 关节内注射（每组 8 只），并跟踪生物发光 4 周。接下来，评估 IDO-Gal3 调节 OA 疼痛和炎症的能力。同样，通过 MCLT+MMT 在雄性 Lewis 大鼠中诱导 OA，在手术后 8 周向 OA 受累膝关节注射 IDO-Gal3 或盐水（每组 7 只）。然后每周评估步态和触觉敏感性。在 12 周时，评估关节内 IL6、CCL2 和 CTXII 水平。
Gal3 融合物增加了 OA 和对侧膝关节的关节停留（p<0.0001）。在 OA 受累动物中，生理盐水和 IDO-Gal3 均改善了触觉敏感性（p=0.008），但 IDO-Gal3 还提高了行走速度（p≤0.033）并改善了垂直地面反作用力（p≤0.04）。最后，IDO-Gal3 降低了 OA 受累关节内的关节内 IL6 水平（p=0.0025）。
关节内 IDO-Gal3 给药为患有 OA 的大鼠提供了对关节炎症和疼痛相关行为的长期调节。
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