Intra-articular celecoxib improves knee extension regardless of surgical release in a rabbit model of arthrofibrosis

Abstract

Aims Outcomes of current operative treatments for arthrofibrosis after total knee arthroplasty (TKA) are not consistently positive or predictable. Pharmacological in vivo studies have focused mostly on prevention of arthrofibrosis. This study used a rabbit model to evaluate intra-articular (IA) effects of celecoxib in treating contracted knees alone, or in combination with capsular release. Methods A total of 24 rabbits underwent contracture-forming surgery with knee immobilization followed by remobilization surgery at eight weeks. At remobilization, one cohort underwent capsular release (n = 12), while the other cohort did not (n = 12). Both groups were divided into two subcohorts (n = 6 each) – one receiving IA injections of celecoxib, and the other receiving injections of vehicle solution (injections every day for two weeks after remobilization). Passive extension angle (PEA) was assessed in live rabbits at 10, 16, and 24 weeks, and disarticulated limbs were analyzed for capsular stiffness at 24 weeks. Results IA celecoxib resulted in greater mean PEA at ten weeks (69.6° (SD 4.6) vs 45.2° (SD 9.6), p = 0.004), 16 weeks (109.8° (SD 24.2) vs 60.9° (SD10.9), p = 0.004), and 24 weeks (101.0° (SD 8.0) vs 66.3° (SD 5.8), p = 0.004). Capsular stiffness was significantly reduced with IA celecoxib (2.72 Newton per cm (N·cm)/° (SD 1.04), p = 0.008), capsular release (2.41 N·cm/° (SD 0.80), p = 0.008), and capsular release combined with IA celecoxib (3.56 N·cm/° (SD 0.99), p = 0.018) relative to IA vehicle (6.09 N·cm/° (SD 1.64)). Conclusion IA injections of a celecoxib led to significant improvements in passive extension angles, with reduced capsular stiffness, when administered to rabbit knees with established experimental contracture. Celecoxib was superior to surgical release, and the combination of celecoxib and a surgical release did not provide any additional value. Cite this article: Bone Joint Res 2022;11(1):32–39.

The epigenetic regulator BRD4 is required for myofibroblast differentiation of knee fibroblasts

“…Interestingly, it has been shown that targeting of BET proteins may also exert anti‐fibrotic activities by reducing the activation of the inflammatory cascade 71,72 . The connection between inflammation, fibrosis, and BET proteins is especially of interest to our group as our studies have previously shown that targeting the inflammatory cascade alleviates contracture formation in a rabbit model of arthrofibrosis 73–75 . The connection between inflammation and local BET protein inhibition is also supported by a study which showed that delivery of JQ1 into the knee alleviates osteoarthritis in mice 76 .…”

“…71,72 The connection between inflammation, fibrosis, and BET proteins is especially of interest to our group as our studies have previously shown that targeting the inflammatory cascade alleviates contracture formation in a rabbit model of arthrofibrosis. [73][74][75] The connection between inflammation and local BET protein inhibition is also supported by a study which showed that delivery of JQ1 into the knee alleviates osteoarthritis in mice. 76 Collectively, these observations suggest that targeting BET proteins alone or in combination with antiinflammatory agents within the local knee environment in established rat 77 and rabbit models 78 of arthrofibrosis could be explored in the future.…”

AdipoRon reduces TGFβ1‐mediated collagen deposition in vitro and alleviates knee stiffness in vivo

“…In the future, it may also be possible to combine AdipoRon therapy with MUA alone or in combination with other potential anti-arthrofibrotic therapies, including the nonsteroidal anti-inflammatory drug celecoxib (Limberg et al, 2020;Salib et al, 2019;Trousdale et al, 2018Trousdale et al, , 2022. However, in our rabbit model of arthrofibrosis, celecoxib was superior to surgical capsular release (used in rabbits as a proxy for MUA), and the combination of celecoxib and a surgical release did not provide additive benefits (Trousdale et al, 2022). While biomechanical testing in mouse and rabbit knees (i.e., PEA at a particular torque) is not directly comparable to the clinical range of motion in patients, the PEA improvement observed in our mouse model of arthrofibrosis in the present study may provide evidence that activation of the adiponectin axis may be a potential therapeutic option in the prevention and treatment of knee arthrofibrosis, alone or in combination with other therapeutics and MUA.…”

“…Biomechanical testing of experimental and contralateral knees was performed as previously described (Dagneaux et al, 2023). A similar approach has also been used to evaluate the arthrofibrotic phenotype in rats and rabbits (Nesterenko et al, 2009; Owen et al, 2022; Trousdale et al, 2022). Experimental and contralateral limbs were disarticulated at the hip and midfoot joints (immobilization suture removed for the no remobilization group), skin and subcutaneous tissues removed, and muscular tissues detached from the proximal third of the femur and tibia.…”

Arthrofibrosis After Total Knee Arthroplasty

“…It is important to note that neither the study by Premkumar et al nor that by Salmons et al reports or makes suggestions on dosages of these medications. Additional support for the use of NSAIDs may be found in recent animal studies that have shown promising results of intra-articular injections of celecoxib in the prevention of joint arthrofibrosis 137,138 .…”