Effects of risk factors on evoked pain patterns in rat models of experimental knee osteoarthritis

Abstract

Pain experiences in patients with knee osteoarthritis (OA) may be influenced differently by OA risk factors, reducing the translatability of preclinical research into the clinic. Our objective was to contrast evoked pain patterns after exposure to different OA risk factors including acute joint trauma, chronic instability, or obesity/metabolic syndrome using rat models of experimental knee OA. We tested longitudinal patterns of evoked pain behaviors (knee pressure pain threshold and hindpaw withdrawal threshold) in young male rats exposed to different OA‐inducing risk factors including (1) nonsurgical joint trauma (impact‐induced anterior cruciate ligament (ACL) rupture); (2) surgical joint destabilization (ACL + medial meniscotibial ligament transection); and (3) high fat/sucrose (HFS) diet‐induced obesity. Histopathology for synovitis, cartilage damage, and subchondral bone morphology was performed. Pressure pain threshold was reduced (more pain) most, and earlier by joint trauma (Week 4–12) and HFS (Week 8–28) than by joint destabilization (Week 12). Hindpaw withdrawal threshold was reduced transiently after joint trauma (Week 4), with smaller and later reductions after joint destabilization (Week 12), but not with HFS. Synovial inflammation occurred at Week 4 after joint trauma and instability but only coincided with pain behaviors after joint trauma. Cartilage and bone histopathology were most severe after joint destabilization and least severe with HFS. The pattern, intensity, and timing of evoked pain behaviors varied due to OA risk factor exposure and were inconsistently associated with histopathological OA features. These findings may help to explain the challenges with translating preclinical OA pain research to multimorbid clinical OA contexts.

Targeting STAT6-mediated synovial macrophage activation improves pain in experimental knee osteoarthritis

“…Mechanical sensitivity at the knee was measured longitudinally in all animals in the 12-week endpoint group (n=10 per condition) as previously described [ 28 ]. Briefly, a pressure application measurement (PAM) algometer (Bioseb) was placed on the medial joint line of the knee and pressure was applied at approximately 200 grams per second until a withdrawal or vocalization occurred.…”

“…Using the same measurement approach as above, ipsilateral hindpaw mechanosensitivity was measured longitudinally in all 12-week endpoint rats as previously described [ 28 ]. Briefly, force was applied to the plantar surface of the hindpaw by the applicator tip of an electronic von Frey instrument (Bioseb).…”

“…Whole knees were harvested for histopathology analysis at 4- and 12-week endpoints from half of the rats included in the liposome treatment cohort (n=5 per condition), fixed, processed, sectioned, and stained with either toluidine blue or haematoxylin & eosin (H&E) as previously described [ 28 ]. Toluidine blue-stained sections (3 per animal, collected every ~600 μm to span the mid-tibiofemoral joint) were used for grading using the OARSI Histopathology cartilage degeneration system [ 29 ].…”

“…Mechanical sensitivity measures were analyzed using linear mixed effects regression models for each treatment group (Veh-lip, Clod-lip, STAT1i-lip, STAT6i-lip) as previously described [ 28 ]. Using separate models for each behavior tested, time was entered as a categorical predictor variable for fixed effects and animal ID was entered as random intercepts.…”