Pathology-pain relationships in different osteoarthritis animal model phenotypes: it matters what you measure, when you measure, and how you got there

Objective: To determine whether osteoarthritis (OA) pain characteristics and mechanistic pathways in pre-clinical models are phenotype-specific. Design: Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA), vs sham-surgery/immunised-controls (Sham/Im-CT). Pain behaviour (allodynia, mechanical- and thermal-hyperalgesia, hindlimb static weight-bearing, stride-length) and lumbar dorsal root ganglia (DRG) gene-expression were measured at baseline, day-3, week-1/-2/-4/-8/-16, and pain-behaviour:gene-expression:joint-pathology associations investigated. Results: DMM and AIA induced structural OA defined by progressively increasing cartilage erosion, subchondral bone sclerosis and osteophyte size and maturation. All pain-behaviours were modified, with model-specific differences in severity and temporal pattern. Tactile allodynia developed acutely in both models and persisted to week-16. During early-OA (wk4-8) there was; reduced right hindlimb weightbearing in AIA; thermal-hyperalgesia and reduced stride-length in DMM. During chronic-OA (wk12-16); mechanical-hyperalgesia and reduced right hindlimb weight-bearing were observed in DMM only. There were no associations in either model between different pain-behaviour outcomes. A coordinated DRGexpression profile was observed in sham and Im-CT for all 11 genes tested, but not in AIA and DMM. At wk-16 despite equivalent joint pathology, changes in DRG-expression (Calca, Trpa1, Trpv1, Trpv4) were observed only in DMM. In AIA mechanical-hyperalgesia was associated with Trpv1 (r = -0.79) and Il1b (r = 0.53). In DMM stride-length was associated with Calca, Tac1, Trpv1, Trpv2, Trpv4 and Adamts5 (r = 0.4 -0.57). DRG gene-expression change was correlated with subchondral-bone sclerosis in DMM, and cartilage damage in AIA. Positive pain-behaviour:joint-pathology associations were only present in AIA for synovitis, subchondral-bone resorption, chondrocyte-hypertrophy and cartilage damage. Conclusion: Pain and peripheral sensory neuronal responses are OA-phenotype-specific with distinct pathology:pain-outcome:molecular-mechanism relationships. (c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Automated summary

The study aimed to determine whether osteoarthritis pain characteristics and mechanistic pathways in pre-clinical models are phenotype-specific. The results showed that pain and peripheral sensory neuronal responses in osteoarthritis are phenotype-specific with distinct pathology:pain-outcome:molecular-mechanism relationships.