Persistent synovial inflammation plays important roles in persistent pain development in the rat knee before cartilage degradation reaches the subchondral bone

Abstract

BackgroundThe major complaint of knee osteoarthritis (OA) is persistent pain. Unlike acute inflammatory pain, persistent pain is usually difficult to manage since its pathology is not fully understood. To elucidate the underlying mechanisms of persistent pain, we established 2 different inflammation-induced arthritis models by injecting monoiodo-acetic acid (MIA) into the joint cavity and performed integrated analyses of the structural changes in the synovial tissue and articular cartilage, sensory neuron rearrangement, and pain avoidance behavior in a rat arthritis model.MethodsMale Wistar rats received intra-articular injections of MIA (0.2 mg/30 μL, low-dose group; 1 mg/30 μL, high-dose group) in the right knee and phosphate buffered saline (PBS; 30 μL, control group) in the left knee. Fluorogold (FG), a retrograde neural tracer, was used to label the nerve fibers for the identification of sensory neurons that dominate the joints in the dorsal root ganglion (DRG). Both knees were subjected to the intra-articular injection of 2% FG in PBS (5 μL) under anesthesia 5–7 days prior to sacrifice. We performed pain avoidance behavior tests (incapacitance and von Frey tests) at 0, 1, 3, 5, 7, 14, 21, and 28 days. At 5, 14, and 28 days, the rats were sacrificed and the knee joint and DRG were excised for histological assessment. The knee joints were stained with hematoxylin and eosin, safranin O, and calcitonin gene-related peptide (CGRP). The DRG were immunostained with CGRP.ResultsA transient inflammatory response followed by mild articular cartilage degeneration was observed in the low-dose MIA model versus persistent inflammation with structural changes in the synovial tissue (fibrosis) in the high-dose model. In the high-dose model, full-thickness cartilage degeneration was observed within 2 weeks post-MIA injection. The pain avoidance behavior tests indicated that persistent synovial inflammation and structural changes of the infrapatellar fat pad may play important roles in persistent knee joint pain before the articular cartilage degeneration reaches the subchondral bone.ConclusionsTransient inflammation without structural changes of the synovial tissues did not induce persistent pain in the rat knee joint before degradation of the articular cartilage reached the subchondral bone plate.Electronic supplementary materialThe online version of this article (10.1186/s12891-018-2221-5) contains supplementary material, which is available to authorized users.

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

“…On the other hand, we have shown that joint damage and pain behavior develop similarly after DMM in both male and female C57/BL6 mice [132]. However, TRPV-1 antagonist capsazepine significantly reduced DMM-induced pain and the expression of TRPV-1 in DRG only in male mice [103]. In another study that used DMM in C57BL/6 mice, although OA changes were evident in 12-month-old females, the extents of cartilage degradation, subchondral bone plate sclerosis, and osteophytes were milder than in males [78].…”

“…The collagenase-induced OA (CIOA) model, which is induced by chemical instability resulting from intra-articular injection of collagenase, also exhibits pronounced synovitis and early exhibition of thermal hyperalgesia, manifesting as early as 1 week after injection [61], while DMM mice do not exhibit thermal hyperalgesia until the late phase of the disease [95]. Persistent inflammation with fibrosis in the synovial tissue of MIA model was accompanied by pain avoidance behavior before articular cartilage degeneration and by an increase in calcitonin gene-related peptide (CGRP)-positive fibers in the DRG and synovium [103]. CIOA induced an increase in interferon regulatory factor 4 (IRF-4), CCL-17 and chemokine (c-c motif) receptor 4 (CCR-4), the CCL-17 receptor; gene-deficient mice were protected from pain as well as joint destruction, indicating that these molecules are required for the development of OA pain [104].…”

Time course analyses of structural changes in the infrapatellar fat pad and synovial membrane during inflammation-induced persistent pain development in rat knee joint

“…Intra-articular injection of MIA is a well-characterized animal model for inflammation-induced OA [8–11]. By using this model, we have reported two different inflammation-induced articular cartilage degeneration models in rats [12, 13]. One is the low-dose model (0.2 mg), in which acute inflammation was observed within 3 days, peaked at 5 days, then alleviated after 7 days [12, 13].…”

“…By using this model, we have reported two different inflammation-induced articular cartilage degeneration models in rats [12, 13]. One is the low-dose model (0.2 mg), in which acute inflammation was observed within 3 days, peaked at 5 days, then alleviated after 7 days [12, 13]. In this model, we observed slow progression of articular cartilage degeneration after 28 days without apparent synovial inflammation after 14 days [12, 13].…”

“…One is the low-dose model (0.2 mg), in which acute inflammation was observed within 3 days, peaked at 5 days, then alleviated after 7 days [12, 13]. In this model, we observed slow progression of articular cartilage degeneration after 28 days without apparent synovial inflammation after 14 days [12, 13]. The other is the high-dose (1.0 mg) model, in which the onset of acute inflammation was comparable with that of the low-dose model; however, obvious irreversible structural changes in the synovial membrane and IFP were observed after 5 days [12, 13].…”