II.

BackgroundOsteoarthritis (OA) is a common joint disease in aging societies, which is accompanied by chronic inflammation and degeneration of the joint structure. Inflammation of the infrapatellar fat pad (IFP) and synovial membrane (IFP surface) plays essential roles in persistent pain development in patients with OA. To identify the point during the inflammatory process critical for persistent pain development, we performed a time course histological analysis in a rat arthritis model.MethodsWistar rats received single intra-articular injection of monoiodoacetic acid (MIA, 0.2 or 1.0 mg/30 μL) in the right knees or phosphate-buffered saline (PBS, 30 μL) as a control in the left knees. Pain avoidance behaviors (weight-bearing asymmetry and tactile hypersensitivity of the plantar surface of the hind paw) were evaluated on days 0, 1, 3, 5, 7, and 14 after injection. Histological assessments of the knee joint were performed on days 0, 1, 3, 5, and 7 after MIA injection.ResultsWeight-bearing asymmetry was observed along with the onset of acute inflammation in both the low- (0.2 mg) and high-dose (1.0 mg) groups. In the low-dose group, weight-bearing asymmetry was completely reversed on day 10, indicating that joint pain seemed to alleviate between days 7 and 10. In contrast, we observed persistent joint pain after day 10 in the high-dose group. Histological assessments of the high-dose group indicated that the initial sign of inflammatory responses was observed in the perivascular region inside the IFP. Inflammatory cell infiltration from the perivascular region to the parenchymal region of the IFP was observed on day 3 and reached the IFP surface (synovial membrane) on day 7. Extensive fibrosis throughout the IFP was observed between days 5 and 7 after MIA injection.ConclusionOur data indicated that acute joint pain occurs along with the onset of acute inflammatory process. Irreversible structural changes in the IFP, such as extensive fibrosis, are observed prior to persistent pain development. Thus, we consider that this process may play important roles in persistent pain development.Electronic supplementary materialThe online version of this article (10.1186/s12891-018-2391-1) contains supplementary material, which is available to authorized users.

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The infrapatellar fat pad (IFP) contains nerve fiber endings and is considered to play an important role in the perception of knee pain. However, it is unclear whether and to what degree prolonged pain influences the nociceptive role of the IFP. To answer this question, we established a novel rat model of knee pain in which inflammation is restricted to the IFP. Rats received a single intra‐IFP injection of monoiodoacetic acid (MIA) (0.2 mg/10 µL or 1.0 mg/10 µL) in the left knee and a phosphate‐buffered saline (10 µL) injection in the right knee as a control. Pain‐avoidance behavior and histological changes of the knee joint were measured at multiple time points up to 28 days after MIA injection. Histological analysis showed a transient inflammatory response in the IFP body in the 0.2‐mg model, whereas prolonged inflammation followed by fibrotic changes was observed in the 1.0‐mg model. Subtle histological alterations were observed in the articular cartilage and IFP surface regardless of the dose. The pain‐avoidance behavior test indicated the development of prolonged knee pain throughout the experimental period in the 1.0‐mg group. Histological assessments showed a significant increase in calcitonin gene‐related peptide (CGRP)‐positive nerve fiber endings inside IFPs with fibrosis in newly vascularized surrounding regions. These data suggest that irreversible fibrotic changes in the IFP induce the formation of new vessels and CGRP‐positive nerve fiber endings that associate prolonged pain in the joint.