# Controlling Joint Instability Reduces Inflammatory Pain in Early Knee Osteoarthritis

## TL;DR

This study shows that reducing joint instability in early knee osteoarthritis can help suppress inflammatory pain, as indicated by changes in pain-related factors in spinal cord cells.

## Contribution

The study demonstrates that joint instability suppression reduces inflammatory pain in early knee OA by affecting calcitonin gene-related peptide (CGRP) expression in dorsal root ganglion cells.

## Key findings

- Knee joint instability was highest in the OA group compared to the CAM and sham groups.
- CGRP expression in the DRG was elevated in the OA group at four weeks post-surgery.
- Reducing joint instability suppressed inflammatory pain but did not significantly affect neuropathic pain markers.

## Abstract

Background and aim

Knee osteoarthritis (OA) is characterized by joint deformity and pain, both of which exert physical and psychological effects on affected individuals. The pain that often appears in the early stages is influenced by the production of inflammatory pain-related factors that respond to nociceptive stimulation from the periarticular tissues. These factors are expressed in small cells within the dorsal root ganglion (DRG) of the spinal cord. Furthermore, neuropathic pain involved in knee OA pain is influenced by neuropathic pain-related factors expressed in DRG small and medium cells, as well as inflammatory pain-related factors expressed in medium cells, which induce chronic pain. However, how these pain-related factors change during the progression of knee OA remains unclear. In addition, joint instability accelerates the progression of knee OA. Reduction of instability reduces mechanical stimulation and delays cartilage degeneration. However, the effect of pain suppression is unknown and requires further investigation. This study aimed to clarify some of the pathological changes in pain generation in the knee OA stage and verify the effect of joint instability suppression on pain reduction.

Materials and methods

Forty-seven adult Wistar rats were divided into OA, controlled abnormal joint movement (CAM), and sham groups, then tissues were collected at four and 12 weeks postoperatively. Knee OA was induced by anterior cruciate ligament transection. In CAM, a tibial suture controlled anterior displacement post-transection. Joint instability was assessed using soft radiography. Histological analysis of the knee joints, fluorescent immunohistochemistry of DRG for inflammatory and neuropathic pain-related factors, and assessments of pain behavior were performed. One-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison test was used to evaluate joint instability and DRG-positive cells-related pain. The Kruskal-Wallis test with Steel-Dwass multiple comparisons was used for histological data. Pain behavior was evaluated using a mixed-design two-way ANOVA.

Results

Knee joint instability was greatest in the OA compared with the CAM and sham. Articular cartilage degeneration was significantly more severe in the OA and CAM than in the sham at both time points. Calcitonin gene-related peptide (CGRP) expression in the DRG was higher in the OA than in the sham at four weeks postoperatively. No significant differences were observed in substance P, isolectin B4, and P2X3 expressions across groups or time points. Pain-related factors were mostly expressed in the small DRG cells. The paw withdrawal thresholds for pain behavior decreased immediately postoperatively, improved by two weeks, and decreased significantly again at 12 weeks postoperatively; however, no significant differences between the groups were noted.

Conclusion

CGRP expression in early knee OA contributes to inflammatory pain, and reacquisition of joint stability suppresses inflammatory pain. In this study, neuropathic pain, including allodynia, was not observed in advanced knee OA.