Noninvasive Mechanical Joint Loading as an Alternative Model for Osteoarthritic Pain

Heegde, Freija ter; Luiz, Ana Paula; Santana-Varela, Sonia; Chessell, Iain P.; Welsh, Fraser; Wood, John N.; Chenu, Chantal

doi:10.1002/art.40835

Cited by 18 publications

(25 citation statements)

References 49 publications

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“…The bipedal walking model is induced by obligatory bipedal exercise, and pathogenic changes in this model are consistent with the pathology observed in humans [22]. The mechanical joint loading model is induced through vertically compressive loading on the knee and ankle joints, which shows a pathogenesis similar to human OA [44]. The STR/ort mouse develops spontaneous OA at a young age [45], whereas other mouse strains are relatively resistant to the spontaneous development of OA [46].…”

Section: Pain In Clinical Oasupporting

confidence: 67%

“…This is reminiscent of human OA, in which pain does not develop, despite advanced joint damage. On the other hand, mechanical joint loading-induced OA animals develop a robust pain phenotype, except for thermal hyperalgesia [44]. Table 1 briefly summarizes the pathology and pain behaviors reported in OA models [38,.…”

Section: Behavioral Tests To Assess Pain In Oa Animal Modelsmentioning

confidence: 99%

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Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

Hong

Park

Kim

2020

IJMS

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Arthritis, including osteoarthritis (OA) and rheumatoid arthritis (RA), is the leading cause of years lived with disability (YLD) worldwide. Although pain is the cardinal symptom of arthritis, which is directly related to function and quality of life, the elucidation of the mechanism underlying the pathogenesis of pain in arthritis has lagged behind other areas, such as inflammation control and regulation of autoimmunity. The lack of therapeutics for optimal pain management is partially responsible for the current epidemic of opioid and narcotic abuse. Recent advances in animal experimentation and molecular biology have led to significant progress in our understanding of arthritis pain. Despite the inherent problems in the extrapolation of data gained from animal pain studies to arthritis in human patients, the critical assessment of molecular mediators and translational studies would help to define the relevance of novel therapeutic targets for the treatment of arthritis pain. This review discusses biological and molecular mechanisms underlying the pathogenesis of arthritis pain determined in animal models of OA and RA, along with the methodologies used.

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Section: Pain In Clinical Oasupporting

confidence: 67%

Section: Behavioral Tests To Assess Pain In Oa Animal Modelsmentioning

confidence: 99%

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

Hong

Park

Kim

2020

IJMS

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“…In previous work, we showed that the mechanical joint loading model at 9N induces a progressive and chronic pain phenotype from two weeks post-loading, characterized by the development of ipsilateral mechanical hypersensitivity, altered weight bearing and reduced mobility, without affecting thermal sensitivity [20]. Here, we used this model to gain insight into how the development of OA pathology in different tissues relates to the development of MJL-induced allodynia [20].…”

Section: Introductionmentioning

confidence: 99%

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

Heegde

Luiz

Santana-Varela

et al. 2020

Osteoarthritis and Cartilage

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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.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Background: Rupture of the anterior cruciate ligament (ACL) is a well-known risk factor for the development of posttraumatic osteoarthritis (PTOA), but patients with the “same injury” can have vastly different trajectories for the onset and progression of disease. Minor subcritical injuries preceding the critical injury event may drive this disparity through preexisting tissue pathologies and sensory changes. Purpose: To investigate the role of subcritical injury on ACL rupture risk and PTOA through the evaluation of pain behaviors, joint mechanics, and tissue structural change in a mouse model of knee injury. Study Design: Controlled laboratory study. Methods: Ten-week-old male C57BL/6J mice were allocated to naïve control and subcritical knee injury groups. Injury was induced by a single mechanical compression to the right hindlimb, and mice were evaluated using joint histopathology, anteroposterior joint biomechanics, pain behaviors (mechanical allodynia and hindlimb weightbearing), and isolated ACL tensile testing to failure at 1, 2, 4, or 8 weeks after injury. Results: Subcritical knee injury produced focal osteochondral lesions in the patellofemoral and lateral tibiofemoral compartments with no resolution for the duration of the study (8 weeks). These lesions were characterized by focal loss of proteoglycan staining, cartilage structural change, chondrocyte pathology, microcracks, and osteocyte cell loss. Injury also resulted in the rapid onset of allodynia (at 1 week), which persisted over time and reduced ACL failure load ( P = .006; mean ± SD, 7.91 ± 2.01 N vs 9.37 ± 1.01 N in naïve controls at 8 weeks after injury), accompanied by evidence of ACL remodeling at the femoral enthesis. Conclusion: The present study in mice establishes a direct effect of a single subcritical knee injury on the development of specific joint tissue pathologies (osteochondral lesions and progressive weakening of the ACL) and allodynic sensitization. These findings demonstrate a predisposition for secondary critical injuries (eg, ACL rupture) and an increased risk of PTOA onset and progression (structurally and symptomatically). Clinical Relevance: Subcritical knee injuries are a common occurrence and, based on this study, can cause persistent sensory and structural change. These findings have important implications for the understanding of risk factors of ACL injury and subsequent PTOA, particularly with regard to prevention and management strategies following an often underreported event.

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Noninvasive Mechanical Joint Loading as an Alternative Model for Osteoarthritic Pain

Cited by 18 publications

References 49 publications

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

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

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

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