Biomechanical, histological, and molecular characterization of a new posttraumatic model of arthrofibrosis in rats

Abstract

Experimental analyses of posttraumatic knee arthrofibrosis utilize a rabbit model as a gold standard. However, a rodent model of arthrofibrosis offers many advantages including reduced cost and comparison with other models of organ fibrosis. This study aimed to characterize the biomechanical, histological, and molecular features of a novel posttraumatic model of arthrofibrosis in rats. Forty eight rats were divided into two equal groups. An immobilization procedure was performed on the right hind limbs of experimental rats. One group was immobilized for 4 weeks and the other for 8 weeks. Both groups were remobilized for 4 weeks. Limbs were studied biomechanically via assessment of torque versus degree of extension, histologically via whole knee specimen, and molecularly via gene expression of posterior capsular tissues. Significant differences were observed between experimental and control limbs at 4 N-cm of torque in the 4-week (knee extension: 115°± 8°vs. 169°± 17°, respectively; p = 0.007) and 8-week immobilization groups (knee extension: 99°± 12°vs. 174°± 9°, respectively; p = 0.008). Histologically, in each group experimental limbs demonstrated increased posterior capsular thickness and total area of tissue when compared to control limbs (p < 0.05). Gene expression values evaluated in each group were comparable. This study presents a novel rat model of arthrofibrosis with severe and persistent knee contractures demonstrated biomechanically and histologically. Statement of clinical significance: Arthrofibrosis is a common complication following contemporary total knee arthroplasties. The proposed model is reproducible, cost-effective, and can be employed for translational investigations studying the pathogenesis of arthrofibrosis and efficacy of neoadjuvant pharmacologic agents.

Human outgrowth knee fibroblasts from patients undergoing total knee arthroplasty exhibit a unique gene expression profile and undergo myofibroblastogenesis upon TGFβ1 stimulation

“…Studies that examine the onset and development of arthrofibrosis effectively utilize animal models by the application of surgical processes to induce the fibrosis in vivo. 13,14 While animal models of arthrofibrosis resemble the human pathophysiology to some degree, 44 investigation of the molecular and cellular mechanisms of human arthrofibrosis requires the use of patient-derived fibroblastic cells for fundamental experimentation in vitro. 20 Use of primary cells is frequently limited by availability, limited proliferative potential (i.e., senescence), interpatient variability, and ethical considerations, 44 while a number of human fibroblast cell lines of uncertain provenance are already commercially available.…”

“…Studies that examine the onset and development of arthrofibrosis effectively utilize animal models by the application of surgical processes to induce the fibrosis in vivo 13,14 . While animal models of arthrofibrosis resemble the human pathophysiology to some degree, 44 investigation of the molecular and cellular mechanisms of human arthrofibrosis requires the use of patient‐derived fibroblastic cells for fundamental experimentation in vitro 20 .…”

“…There is some limited data on pharmacologic treatments for arthrofibrosis, but these studies were exclusively performed in vivo using animal models. [13][14][15] However, in vivo models of arthrofibrosis are costly, and the ability to control specific regulatory molecular pathways that contribute to the disease process is limited. To date, there are few in vitro options that are suitable to study myofibroblastogenesis, and these utilize fibroblasts derived from unknown sources, 16,17 cells from human tissues not associated with the local knee environment, 18 knee fibroblasts isolated from animals, 19 or primary cells isolated from the human knee environment with only partial phenotypic characterization.…”

“…From clinical and translational perspectives, it would be a major advancement if arthroplasty surgeons could identify and prophylactically treat individuals at risk for arthrofibrosis. There is some limited data on pharmacologic treatments for arthrofibrosis, but these studies were exclusively performed in vivo using animal models 13–15 . However, in vivo models of arthrofibrosis are costly, and the ability to control specific regulatory molecular pathways that contribute to the disease process is limited.…”

Pleiotropic Long-Term Effects of Atorvastatin on Posttraumatic Joint Contracture in a Rat Model

“…The present study has some limitations. In two recently published studies on posttraumatic contracture in rats, the influence of cartilage and ligaments was described both during immobilization and especially during remobilization [ 33 , 54 ]. Dunham et al stated that ligaments and cartilage are mostly responsible for the motion loss after remobilization and that the contribution of the capsule to joint contracture accounts for only 26% after 6 weeks of remobilization.…”