Impaired Function and in vivo Imaging of NF-κB Activation in a Mouse Model of Knee Joint Inflammation

Abstract

Objective: Osteoarthritis (OA) is a consequence of not only mechanical events such as joint instability, but also biological events that result in the upregulation of proinflammatory and catabolic mediators. The intra-articular injection of monoiodoacetate (MIA) has been widely used to induce OA. NF-B activity has been linked to increased expression of proinflammatory cytokines (IL-1, TNF-, IL-6, etc), metalloproteinases (MMPs), chemokines and inducible enzymes, which all contribute to cartilage degradation and subsequent OA. The goal of this study was to use in vivo imaging (IVIS) of NF-B activation to track longitudinal changes due to inflammation in a rodent model of OA. Design: Twenty-four (24) NF-B-luc reporter transgenic mice [BALB/C-Tg (NF-B-RE-luc)-Xen, age 7-8 weeks] were given intra-articular knee injections with either MIA (n = 12) or normal saline (n = 12) to serve as a control. IVIS and ex vivo imaging of NF-B and tactile allodynia measurements were performed, and correlations were recorded preoperatively and on days 1, 3, 7, 14, 21 and 28. Animals were euthanized on days 3 and 28 for ex vivo imaging, and tissues were stored for future immunohistochemical evaluation. Results: NF-B activity was significantly elevated in the MIA group on days 1 and 3 (p < 0.05) when compared to preoperative levels and was significantly elevated compared to the normal saline group on day 3 (p < 0.05). There was a significant increase in tactile allodynia in the MIA group compared to preoperative levels, as well as compared to the normal saline group at all time points (p < 0.05). In vivo NF-B luminescence correlated with tactile allodynia (p < 0.0001) and with ex vivo imaging (p < 0.0001). Conclusion: This study validates the use of IVIS imaging of NF-B activity in a MIA rodent model of arthritis and provides evidence for the use of NF-B luminescence imaging as an imaging biomarker of pain sensitivities. This can be utilized in the future to further elucidate NF-B's role in inflammation and OA. In addition, it can help evaluate potential therapeutic agents that target NF-B.