Chronic synovial inflammation play important roles to establish residual pain in monoiodoacetic acid induced arthritis rat model

Abstract

Purpose: Osteoarthritis (OA) is a group of diseases and mechanical abnormalities involving degradation of articular cartilage and subchondral bone. Major complaint of OA patients is persistent knee pain, which significantly decreases patients' activity of daily living (ADL). However, causal treatment has not provided for OA patients since OA is multifactorial diseases and etiology has not fully understood. Therefore, most of the current treatment strategies for OA is based on the symptom management and patients with uncontrolled knee pain usually choose knee replacement surgery. In this regard, we consider it is quite important to understand the mechanisms of persistent knee pain development during the progression of OA. We have established two distinct inflammation-induced articular cartilage degeneration models in rats. The first was to induce joint inflammation by intra-articular injection of low-dose (0.2mg) of monoiodoacetate (MIA). In this model, we observed transient synovial inflammation followed by mild articular cartilage degeneration in rat knee. The other was high-dose (1.0mg) of MIA injection method. In this model, chronic synovial inflammation and extensive articular cartilage degeneration were observed by 14 days after injection. In this study, we performed detailed histological assessments and monitored pain avoidance behavior in these rat models to understand the mechanisms how knee pain persistence established after joint inflammation. Here we showed that chronic synovial inflammation may play important roles to establish residual pain in rats. Methods: Male Wistar rats received intra-articular injection of MIA (0.2mg, or 1mg/30μl) in the right knee, and PBS (30μl) in the left knee. We performed pain behavior test (Incapacitnce Test and von Frey Test) at 0,1,3,5,7,14,21, and 28 days. At 5, 14, and 28 days, rats were sacrificed, and knee joint and dorsal root ganglion (DRG) were excised for histological assessments. Results: In the low-dose group (0.2mg), extensive inflammatory cell infiltration in the infra-patella fat pad (IFP) and synovial hyperplasia were observed by 5 days after MIA injection, then quenched by 14 days. Proteoglycan contents in both articular cartilage and meniscus gradually decreased by 28 days. Incapacitance tests indicated that weight-bearing of the MIA injected knee (right knee) was significantly decreased by 7 days after injection and returned to the even levels by 14 days when the acute synovial inflammation was quenched. Percentage of Calcitonin-Gene Related Peptide (CGRP)-positive sensory neuron in L4 DRG was significantly decreased at 28 days if compared to that in day 5. In the high-dose group (1.0mg), onset of inflammatory response was almost the same with that of low-dose group, however, it continued throughout the experimental period (28 days). Signs of articular cartilage degeneration was obviously observed as early as 5 days after injection and superficial layers were almost missing at 28 days. In contrast to the low-dose group, weight-bearing continued decreasing significantly throughout the experimental period. Immunohistochemical analyses indicated that percentage of CGRP-positive sensory neuron was much abundant and did not decrease by 28 days. Conclusions: Data suggest that persistent synovial inflammation plays important roles in establishing residual pain in the knee joint.