Pathological mechanisms and therapeutic outlooks for arthrofibrosis

Abstract

Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury, surgery and infection. Excessive extracellular matrix and adhesions contract pouches, bursae and tendons, cause pain and prevent a normal range of joint motion, with devastating consequences for patient quality of life. Arthrofibrosis affects people of all ages, with published rates varying. The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers. However, current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis. The process begins when stress signals stimulate immune cells. The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts, which secrete fibrillar collagens and transforming growth factor-β (TGF-β). Positive feedback networks then dysregulate processes that normally terminate healing processes. We propose two subtypes of arthrofibrosis occur: active arthrofibrosis and residual arthrofibrosis. In the latter the fibrogenic processes have resolved but the joint remains stiff. The best therapeutic approach for each subtype may differ significantly. Treatment typically involves surgery, however, a pharmacological approach to correct dysregulated cell signalling could be more effective. Recent research shows that myofibroblasts are capable of reversing differentiation, and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments. Therapies with significant promise are currently available, with more in development, including those that inhibit TGF-β signalling and epigenetic modifications. This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments.

<p>Effects of losartan and atorvastatin on the development of early posttraumatic joint stiffness in a rat model</p>

“…Synonyms for this disorder are joint contracture, stiff knee, stiff elbow or arthrofibrosis. 4,5 In our study, PTJS of the knee was defined as a limited passive extension of the knee joint after trauma, which was not caused by incongruency of the joint. Prolonged physiotherapeutic treatment or operative removal of the joint capsule (with certain associated risks) are often capable of improving the range of motion in PTJS.…”

Expression of xylosyltransferases I and II and their role in the pathogenesis of arthrofibrosis

“…However, they are still present, which can lead to the development of a fibrosis. The appearance of an inflammatory cytokine causes the formation of receptors for other cytokines and sensitizes the cells to react [16]. They are also characterized by their high rate of synthesizing components of the extracellular matrix (ECM) like collagens and xylosyltransferases (XT).…”

Sulfasalazine Resolves Joint Stiffness in a Rabbit Model of Arthrofibrosis

“…The standard‐of‐care is limited to arthroscopic debridement, capsule‐release, and manipulating limbs under anesthesia. While these procedures can partially restore joint mobility, 25% of patients suffer recurring fibrosis that necessitates multiple interventions . Thus, there is a need to develop approaches to augment these interventions.…”

“…While these procedures can partially restore joint mobility, 25% of patients suffer recurring fibrosis that necessitates multiple interventions. [7][8][9][10] Thus, there is a need to develop approaches to augment these interventions.…”

“…12,[19][20][21] Capsule contracture from joint immobilization is accompanied by the proliferation of cells lining the synovial intima, 22 which is thought to contribute to capsule hypertrophy by increasing the local secretion of TGF-β1 and pro-inflammatory cytokines. 10 Thus, thickening of the intimal cell layer is part of the profibrotic response to immobilization and is of interest in assessing the effects of anti-fibrotic drugs.…”