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Inhibition of COX-2 Pathway as a Potential Prophylaxis Against Arthrofibrogenesis in a Rabbit Model of Joint
Christopher G Salib1, Nicolas Reina1, William H Trousdale1
1Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota.
Abstract:
Arthrofibrosis is a common complication following total knee arthroplasty caused by pathologic fibroblast activation and excessive collagen deposition around a synovial joint leading to debilitating loss of motion. Treatment options are limited because the pathologic mechanisms remain to be characterized. Dysregulation of the inflammatory cascade may lead to communication between myofibroblasts and immune cells triggering tissue metaplasia, and excessive collagen deposition described clinically as arthrofibrosis. We explored the novel use of celecoxib (selective cyclooxygenase-2 [COX-2] inhibitor) to disrupt the downstream effects of the post-traumatic inflammatory cascade and inhibit scar tissue formation in a validated rabbit model of arthrofibrosis combined with new parameters for quantifying the stiffness of the posterior capsule. Biomechanical and molecular analyses, of contracted rabbit knee posterior capsule tissue after COX-2 inhibition revealed increased maximal passive extension and down-regulation of collagen messenger RNA compared with controls. Histopathologic examination suggested a trend of decreased quantities of dense fibrous connective tissue with COX-2 inhibition. These data may suggest that inhibiting the inflammatory cascade could potentially reduce pathologic myofibroblast activation, thereby reducing scar tissue formation and increasing the range of motion in arthrofibrotic joints. Implementing a multi-modal pharmacologic approach may simultaneously target numerous cellular components contributing to the complex process of arthrofibrogenesis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2609-2620, 2019.
Insights
Celecoxib, a COX-2 inhibitor, reduced scar tissue formation and improved range of motion in a rabbit model of arthrofibrosis. This suggests inhibiting inflammation may treat knee stiffness after surgery.
Area of Science:
- Orthopaedic Surgery
- Biomedical Engineering
- Pharmacology
Background:
- Arthrofibrosis, a complication of total knee arthroplasty, causes significant motion loss due to excessive scar tissue.
- Current treatment options are limited as the underlying mechanisms of arthrofibrosis are not fully understood.
- Inflammation dysregulation may drive myofibroblast activation and collagen deposition, leading to arthrofibrosis.
Purpose of the Study:
- To investigate the efficacy of celecoxib (a selective cyclooxygenase-2 [COX-2] inhibitor) in mitigating arthrofibrosis.
- To assess the impact of COX-2 inhibition on scar tissue formation and joint mobility in a rabbit model.
- To explore the potential of targeting the inflammatory cascade to treat arthrofibrosis.
Main Methods:
- A validated rabbit model of arthrofibrosis was utilized.
- Celecoxib was administered to inhibit the cyclooxygenase-2 (COX-2) pathway.
- Biomechanical testing (maximal passive extension) and molecular analyses (collagen mRNA) were performed on posterior knee capsule tissue.
- Histopathological examination quantified fibrous connective tissue.
Main Results:
- COX-2 inhibition resulted in increased maximal passive extension of the knee joint.
- A significant down-regulation of collagen messenger RNA was observed in the treated group.
- Histopathology indicated a trend towards decreased dense fibrous connective tissue formation.
Conclusions:
- Inhibiting the inflammatory cascade via COX-2 inhibition may reduce myofibroblast activation and subsequent scar tissue formation.
- This approach holds potential for increasing range of motion in arthrofibrotic joints.
- Multi-modal pharmacologic strategies could effectively target key cellular processes in arthrofibrogenesis.
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