Intra-Articular Delivery of an Indoleamine 2,3-Dioxygenase Galectin-3 Fusion Protein for Osteoarthritis Treatment in Male Lewis Rats

Abstract

Objective: Controlling joint inflammation can improve osteoarthritis (OA) symptoms; however, current treatments often fail to provide long-term effects. We have developed an indoleamine 2,3-dioxygenase and galectin-3 fusion protein (IDO-Gal3). IDO converts tryptophan to kynurenines, directing the local environment toward an anti-inflammatory state; Gal3 binds carbohydrates and extends 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. Methods: 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-Gal3’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. Results: The Gal3 fusion increased joint residence in OA and contralateral knees (p<0.0001). In OA-affected animals, IDO-Gal3 improved tactile sensitivity (p=0.002), 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). Conclusion: Intra-articular IDO-Gal3 delivery provided long-term modulation of joint inflammation and pain-related behaviors in rats with established OA.

Identification of osteoblastic autophagy-related genes for predicting diagnostic markers in osteoarthritis

“… 29 This indicates a close association between DEGs and cartilage development. In terms of molecular function (MF), we also observed a decrease in activities of small molecule binding functions, such as tubulin binding 30 , 31 and pyrrole binding 32 in the OA group, while extracellular matrix structural components conferring tensile strength and structural molecule activity were active. This indicates the involvement of DEGs in the production of subchondral bone extracellular matrix and their association with the growth and development of osteoblasts, which is as previously reported.…”