Why does my joint hurt: Understanding disease phenotype and pain relationships using mouse models of arthritis

Abstract

Osteoarthritis (OA), characterised by progressive joint-wide pathology, is a major health problem accounting for 48% of people living with chronic pain. There are no treatments to slow OA progression and symptom managing therapies are at best moderately effective. This failure results from a poor understanding of the mechanisms that drive OA pain. Animal models are widely used to study OA pain molecular pathways, but pre-clinical findings fail to translate into effective therapeutics for patients. In part this may be because animal models have poorly defined phenotypes not mapped to specific sub-types of human OA. This research aimed to define the relationship between joint tissue pathology, pain behaviour and gene expression in the dorsal root ganglia (DRG), over time comparing models of post-traumatic OA (DMM) and inflammatory arthritis (AIA), and identify differences in what drives pain. DMM and AIA ultimately displayed similar hallmark histopathology of OA in late stage disease. However, each model had distinct temporal patterns of pathology; associations between articular cartilage, synovium and bone pathology; and risk factors for progression. Both models displayed sensitisation (tactile allodynia, mechanical and thermal hyperalgesia) and altered gait (reduced hindlimb weight bearing, changes in stride length). However, the severity and temporal pattern of occurrence were model-specific. At each phase of OA development, DRG gene expression changes were also model-specific. It was predominantly synovium and bone pathology that were significantly associated with altered DRG gene expression and pain behavior, but differentially in the two models. The DRG expression changes associated with altered pain behaviours were also model-specific. Combined these findings demonstrate that DMM and AIA are phenotypically unique models of OA, defined not only by initiating cause, but temporal pattern and inter-dependence of joint pathology, pain characteristics, and molecular drivers. The results suggest that the mechanisms regulating joint pain are specific to the disease pathophysiology, and confirm the importance of mapping pre-clinical findings to specific human disease phenotypes. This challenges the current way animal models are used to investigate OA pain mechanisms and test therapeutics.