Cyclooxygenase-2 inhibitor celecoxib attenuates joint contracture following immobilization in rat knees

Abstract

Background: The aim of this study is to clarify the following two points: First, whether a cyclooxygenase-2 mediated pathway is involved in the formation of immobilization-induced joint contracture and, second, the effectiveness of oral administration of non-steroidal anti-inflammatory drug celecoxib (CBX) for the prevention of myogenic and arthrogenic contracture following immobilization in a rat model.

Methods: Thirty male rats were randomly divided into three groups: immobilization (Im), Im + CBX, and control (n = 10 each). External fixation immobilized the right knee joint of Im and Im + CBX groups in flexion for 3 weeks. 50 mg/kg of CBX was administrated daily to the Im + CBX group during this period. The passive range of motion (ROM) of knee joints was measured before and after transection of knee flexor muscles and myogenic and arthrogenic ROM restrictions were calculated. The semitendinosus muscles and knee joints were investigated histologically to elucidate factors responsible for contracture.

Results: Myogenic ROM restrictions were exhibited both in Im and Im + CBX groups (44 ± 5 and 36 ± 8 °, respectively), but restrictions significantly decreased in the Im + CBX group compared to the Im group. Significant reductions of the muscle length ratios (Rt/Lt) and sarcomere number ratios (Rt/Lt) in knee flexor semitendinosus muscle, which are responsible for myogenic contracture, were also seen both in Im group (92 ± 5 and 92 ± 4 %, respectively) and Im + CBX group (97 ± 3 and 97 ± 3 %, respectively), but were inhibited by CBX administration (P < 0.05). Im and Im + CBX groups exhibited arthrogenic ROM restrictions with no significant differences (82 ± 3 and 83 ± 5 °, respectively). Posterior synovial length shortening and pathological changes (hemorrhage in joint cavities and capsule edema) in the knee joints were comparable between Im and Im + CBX groups.

Conclusions: Oral administration of celecoxib partially reduced myogenic ROM restriction concomitantly with knee flexor muscle shortening following immobilization. These results imply that inflammation and nociception are involved in myogenic contracture formation independently of joint immobilization, and that CBX is effective in preventing joint contracture following immobilization in rats.

Keywords: Celecoxib; Immobilization; Joint contracture; Knee; Muscle.

Fig. 1

Photograph of joint immobilization. Knee joint is immobilized by an external fixator at approximately 140 ° flexion (the angle between the femur and the tibia is 40 °)

Fig. 2

Histograms showing changes in passive knee extension ROMs. a ROM before myotomy of knee flexor muscles (ROM+m). Joint immobilization induced ROM+m restrictions in both Im and Im + CBX groups. Celecoxib partially prevented the ROM+m restriction induced by joint immobilization. b ROM after myotomy of knee flexor muscles (ROM-m). Joint immobilization induced ROM-m restrictions in both Im and Im + CBX groups. Celecoxib did not change ROM-m restriction induced by joint immobilization. (Experimental side (Rt), ■; Contralateral side (Lt), □). ^† P < 0.05 vs. contralateral side of the same group; ^# P < 0.05 vs. ipsilateral side of Im group. Data are expressed as means ± SD (n = 10)

Fig. 3

Histograms showing changes in knee extension ROM restriction. a Myogenic restrictions. Celecoxib treatment partially reduced myogenic contracture induced by joint immobilization. b Arthrogenic restriction. Celecoxib treatment did not reduce arthrogenic contracture induced by joint immobilization. *P < 0.05 vs. control group; ^# P < 0.05 vs. Im group. Data are expressed as means ± SD (n = 10)

Fig. 4

Histograms showing morphological changes in the semitendinosus muscles. a Muscle length ratio (experimental side (Rt)/contralateral side (Lt)). b Sarcomere number ratio (experimental side (Rt)/contralateral side (Lt)). Decrease in both muscle length ratio and sarcomere number ratio were partially prevented by celecoxib treatment. *P < 0.05 vs. control group; ^# P < 0.05 vs. Im group. Data are expressed as means ± SD (n = 10)

Fig. 5

Morphological changes in the knee joint. Representative images of the posterior region of the knee with Hematoxylin and Eosin stain in the control group (a, d), Im group (b, e), and Im + BTX group (c, f). Higher magnification of the squared areas in a, c, and e, are shown in b, d, and f, respectively. In the control group, blood cell infiltration was hardly visible in the joint space at inferior capsule-cartilage junctions. In the Im and Im + CBX groups, comparable amounts of red blood cells were present (arrows). g Box plot showing mean values of intra-articular hemorrhage scores. Celecoxib treatment did not prevent joint hemorrhage induced by joint immobilization. ^* P < 0.05 compared with control. h Histogram showing posterior synovial lengths. Celecoxib treatment did not prevent the reduction of synovial length induced by joint immobilization. *P < 0.05 compared with control. Data are expressed as means ± SD (n = 10)