Animal model-specific associations between osteoarthritis pathology and pain – phenotype does matter

Abstract

Purpose: Osteoarthritis (OA) is a complex progressive disease of joints that affects all joint tissues and results in pain and reduced mobility. OA is described in terms of structural and biological joint pathology but the magnitude of the disease burden is measured by the clinical symptoms, pain and immobility. Advanced imaging has identified associations in OA patients between synovitis, bone marrow lesions and pain, but it remains unclear how different joint pathologies drive pain. Importantly, a direct relationship between global joint pathology severity and pain intensity has not been demonstrated, and there is no established cause-effect relationship to explain how joint pathology drives pain. We explored the associations between joint histopathology, pain behaviour and dorsal root ganglia (DRG) gene expression in two distinct arthritis models, to define the pathology/pain relationship and determine if this is phenotype specific. Methods: Male 10-week C57BL6 mice had unilateral medial meniscal destabilisation (DMM), antigen-induced arthritis (AIA), or respective controls (sham surgery, saline injection) (n = 6–12/disease/time). Allodynia, mechanical hyperalgesia, stride length and hind limb weight distribution (HLWD) were measured at baseline, week 1, 2, 4, 8, 12 and 16. At each time knees were harvested, processed and histologically scored for different joint tissue pathologies (synovium, articular cartilage, subchondral bone and osteophyte formation). Expression of mu opioid receptor (Oprm1), interleukin-1b, inflammatory neuropeptides (Tac1, CGRP), nociceptore channels (TRPV1, TRPV2, TRPV4, TRPA1), and aggrecanases (ADAMTS4 and ADAMTS5) were quantified in L3-4 DRG. Associations between outcomes, corrected for time, were determined for each model using Kendall's tau-b. Results: While displaying significantly different temporal patterns of joint tissue pathology, by week 16 both models had equivalent hallmark histopathological features of OA. However, the associations between subchondral bone, osteophytes, synovitis and progression of cartilage erosion were unique to each model. Significant associations between histopathology and pain were positive in DMM (HLWD: synovitis, bone remodeling; Stride length: synovitis) but negative in AIA (PAM: synovitis, cartilage damage, proteoglycan loss; Stride length: synovitis; HLWD: bone remodelling). Synovitis and subchondral bone were the main tissues to demonstrate significant associations with DRG gene expression. Positive associations were found in DMM between stride-length and CGRP, Tac1, TRPV1, TRPV2, TRPV4 and ADAMTS-5; and in AIA between PAM and IL-1b. Conclusions: Despite both models ultimately displaying equivalent OA-pathology, we identified model-specific joint pathology, pain, DRG expression associations. The significant model-specific differences in association between joint tissue histopathology and both pain measures and DRG gene expression, demonstrate that there are unique pain regulatory pathways in each model. These results suggest that the molecular mechanisms that drive joint pain are specific to the underlying pathophysiology of the disease, and therefore differ between different OA phenotypes. This has significant implications for development and pre-clinical testing of phenotype-specific OA pain therapies.