Characteristics of sensory innervation in synovium of rats within different knee osteoarthritis models and the correlation between synovial fibrosis and hyperalgesia

INTRODUCTION: Knee osteoarthritis (KOA) showed synovial fibrosis and hyperalgesia, although the correlation between the two is unclear. Besides, the specific changes of sensory innervation in animal models are still controversial, which makes it difficult to choose the modeling methods for KOA pain research. OBJECTIVES: Study the characteristics of sensory innervation within three commonly used KOA rat models and the correlation between synovial fibrosis and hyperalgesia. METHODS: KOA models were induced by destabilization of medial meniscus (DMM), anterior cruciate ligament transection (ACLT), and monoiodoacetate (MIA), respectively. Mechanical, cold and thermal withdrawal threshold (MWT, CWT and TWT) were measured. The harvested tissues were used for pathological sections, immunofluorescence and quantitative analysis. RESULTS: KOA synovium showed more type I collagen deposition, increased expression of CD31, VEGF and TGF-β. These changes were most pronounced in surgical models, with DMM presenting the most prominent at Day 14 and ACLT at Day 28. Day 14, changes in mechanical hyperalgesia and cold hyperalgesia were most typical in DMM model and statistically different from MIA. There was a negative correlation between the percentage of type I collagen and MWT value (r = −0.88), as well as CWT value (r = −0.95). DMM synovium showed more axonal staining, upregulated CGRP, TRPV1, NGF and Netrin1 compared with MIA. Above changes were also observed at Day 28, but ACLT replaced DMM as the most typical. In DRG, only the levels of CGRP and NGF were different among KOA models at Day 14, and the highest in DMM, which was statistically different compared with MIA. CONCLUSIONS: This study described the details of sensory innervation in different KOA model of rats, and the degree of synovial fibrosis was positively correlated with the pain sensitivity of KOA model rats. Additionally, surgical modeling especially ACLT method is more recommended for KOA pain research.