Osteoarthritis-related nociceptive behaviour following mechanical joint loading correlates with cartilage damage

Abstract

Objective: In osteoarthritis (OA), the pain-structure relationship remains complex and poorly understood. Here, we used the mechanical joint loading (MJL) model of OA to investigate both knee pathology and nociceptive behaviour.Design: MJL was used to induce OA in the right knees of 12-week-old male C57BL/6 mice (40 cycles, 9N, 3x/week for two weeks). Mechanical sensitivity thresholds and weight-bearing ratios were measured before loading and at weeks one, three and six post-loading. At these time points, separate groups of loaded and non-loaded mice (n=12/group) were sacrificed, joints collected, and fur corticosterone levels measured. µCT analyses of subchondral bone integrity was performed before joint sections were prepared for nerve quantification, cartilage or synovium grading (scoring system from 0-6).Results: Loaded mice showed increased mechanical hypersensitivity paired with altered weightbearing. Initial ipsilateral cartilage lesions one-week post-loading (1.8±0.4) had worsened at weeks three (3.0±0.6, CI=-1.8--0.6) and six (2.8±0.4, CI=-1.6--0.4). This increase in lesion severity correlated with mechanical hypersensitivity development (correlation; 0.729, p=0.0071). Loaded mice displayed increased synovitis (3.6±0.5) compared to non-loaded mice (1.5±0.5, CI=-2.2--0.3) one-week postloading which returned to normal by weeks three and six. Similarly, corticosterone levels were only increased at week one post-loading (0.21±0.04ng/mg) compared to non-loaded controls (0.14±0.01ng/mg, CI=-1.8--0.1). Subchondral bone integrity and nerve volume remained unchanged.Conclusions: Our data indicates that although the loading induces an initial stress reaction and local inflammation, these processes are not directly responsible for the nociceptive phenotype observed.Instead, MJL-induced allodynia is mainly associated with OA-like progression of cartilage lesions.

NF-κB-mediated effects on behavior and cartilage pathology in a non-invasive loading model of post-traumatic osteoarthritis

“…Similarly, surgical destabilization models of PTOA consistently result in hindpaw allodynia when compared to sham operated animals; however, the onset, presentation, and duration of hindpaw allodynia is varied and different from that observed in this non-invasive PTOA model 29,32,33 . Recent work by Heegde and colleagues corroborates the findings of the current study and shows that mechanicallyinduced joint injury is associated with both acute onset and maintenance of hindpaw allodynia 34 .…”

Long-term Effect of a Single Subcritical Knee Injury: Increasing the Risk of Anterior Cruciate Ligament Rupture and Osteoarthritis

“…Similar mechanical sensitization has been reported after repetitive cyclical subcritical loading in mice. 66 However, consistent with induction of PTOA, repetitive injury caused altered hindlimb weightbearing and reduced mobility; furthermore, pain-related behavior, particularly mechanical sensitization, was correlated with progression of tibiofemoral cartilage damage. 65,66 One hypothesized driver of this association is the accompanying neurovascularization of the osteochondral junction, a feature observed in osteoarthritic joints.…”

“…66 However, consistent with induction of PTOA, repetitive injury caused altered hindlimb weightbearing and reduced mobility; furthermore, pain-related behavior, particularly mechanical sensitization, was correlated with progression of tibiofemoral cartilage damage. 65,66 One hypothesized driver of this association is the accompanying neurovascularization of the osteochondral junction, a feature observed in osteoarthritic joints. 61 Osteoclast activity is one aspect of this process, with a recent mouse study demonstrating reduced joint innervation and pain responses when subchondral bone remodeling was inhibited.…”

“…Repetitive cyclical knee loading did not alter the density of sensory or sympathetic nerves in any of the joint tissues examined, including the ACL. 66 Studies are needed to determine (1) if the increased sensitization results from altered joint innervation and distribution at the ACL entheses and within the patellofemoral compartment, and (2) whether this is a response to injury and/or a compounded effect caused by direct neural disruption from traumatic loading of the joint. Importantly, altered sensorimotor inputs are recognized contributing factors for ACL rupture risk and PTOA progression, likely through impaired functional control of the joint.…”

Acupotomy Contributes to Suppressing Subchondral Bone Resorption in KOA Rabbits by Regulating the OPG/RANKL Signaling Pathway

“…Subchondral bone lesions will weaken its mechanical strength and the ability to buffer mechanical stress accordingly [29], which increases the risk of cartilage injury and accelerates the KOA process. Previous studies have found that the increased subchondral bone loss was positively correlated with the level of cartilage erosion in KOA [30,31].…”