Inhibition of COX‐2 Pathway as a Potential Prophylaxis Against Arthrofibrogenesis in a Rabbit Model of Joint Contracture

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.

Reduction of arthrofibrosis utilizing a collagen membrane drug‐eluting scaffold with celecoxib and subcutaneous injections with ketotifen

“…The range of tissue findings on both H&E and α-SMA staining Outcomes of the present study corroborate previous results from our group demonstrating decreased contracture severity after intra-articular administration of the COX-2 inhibitor CXB via repeated intra-articular injections. 10 In the current study, we identified decreased COL3A1, COL6A1, and ACTA2 mRNA expression in all treatment arms when compared to the contracture control group (group 1). We hypothesize that this likely results from early inhibition of the pro-inflammatory cascade and continues during the collagen membrane absorption phase (which has been reported to take approximately 8 weeks).…”

“…5 In addition, significant differences were detected in the messenger RNA (mRNA) expression of collagen markers COL1A1, COL3A1, and COL6A1 (Figure 4) within periarticular soft tissues near the surgically manipulated joint, as has been noted previously. 10 However, COL1A1…”

“…3,8 Utilizing a clinically relevant rabbit model, we have demonstrated the development of a durable contracture, early increases in myofibroblasts, increased extracellular matrix (ECM) deposition, and changes in the molecular landscape. 3,5,6,9,10 Using this animal model, several pharmacologic agents have been trialed as possible therapies for this condition. These have included ketotifen fumarate, decorin, rosiglitazone, and a substance P inhibitor.…”

“…17 In previous studies, local administration of CXB was performed via repeated intra-articular injections. 10 However, multiple intra-articular injections over a short period are cumbersome and may result in repetitive microtrauma that could, in and of itself, be pro-fibrotic. This has made the isolation of a potential effect from CXB somewhat more challenging.…”

“…reaction (qPCR). 10 Before assessing expression levels of the genes of interest, each sample was tested for contamination of bone, skeletal muscle, blood, and fat using qPCR. If contamination was detected, the sample was excluded from all further analyses.…”