Pathological mechanisms and therapeutic outlooks for arthrofibrosis


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.


Arthrofibrosis is a fibrotic joint disorder characterised by excessive collagen production and adhesions that result in restricted joint motion and pain. It can occur in most joints,1 and is referred to by a number of names including frozen shoulder, adhesive capsulitis, joint contracture, stiff knee and stiff elbow. Sterile arthrofibrosis is typically caused by chronic or repetitive injury or surgery that leads to a dysregulated immune reaction and fibrosis in and/or around a joint2 to varying degrees. The fibrotic scar tissue that forms in the joint is known as extracellular matrix (ECM), and is primarily composed of collagen. Although the term ECM includes a wide variety of biological components we use this established terminology when discussing fibrotic scar tissue. This forms adhesions within joint capsules and contracts tendons and bursa around the joint,3 causing the loss of joint flexion and/or extension. In addition, scarred bursa may impinge into the joint causing more inflammation. Together with reduced range of motion (ROM), pain and varying amounts of swelling are commonly reported by patients. Arthrofibrosis affects people of all ages, although it is rare in children.4
Arthrofibrosis frequently causes significant disability; however, the nature of the disability depends on the joint affected and disease severity. When arthrofibrosis affects the knee symptoms become intensified during walking and standing, and the condition is frequently more debilitating than the original injury or degenerative condition.5 Even a small loss of knee extension of 5° creates difficulties in walking while a loss of flexion creates problems with stair climbing, sitting, getting in and out of chairs6 and cars and driving. Papers sometimes state that arthrofibrosis is a “frustrating” or “disappointing” problem for both surgeon and patient,7,8,9,10,11 however, these descriptions do not adequately describe the effects that arthrofibrosis has on patients’ lives. Patients frequently suffer constant pain, severe limitations on physical activity and difficulty sleeping, sitting and weight bearing.12 These symptoms may lead to the loss of job/career and difficulty socialising and performing daily living tasks, negatively impacting physical and emotional well-being.
On a cellular level arthrofibrosis is characterised by upregulated myofibroblast proliferation with reduced apoptosis, adhesions, aggressive synthesis of ECM that can fill and contract joint pouches and tissues and often also heterotrophic ossification.1,13,14 Although ECM is necessary for healing and wound repair, dysregulation of production and degradation leads to pathologic fibrosis.1,15 While there are relatively few studies into the pathogenesis and molecular biology of arthrofibrosis compared to other fibrotic diseases,1 there are common pathogenic pathways.16,17,18
This review highlights current progress in understanding the pathogenesis of sterile arthrofibrosis, focusing on arthrofibrosis of the knee to illustrate the condition. The regulation of inflammation, myofibroblast proliferation and survival and ECM production involves a highly complex array of mediators, cell types, receptors and interactions. A detailed explanation of all of these factors is beyond the scope of this review; therefore, we present a summary of the important cytokines and mediators involved in the condition. In addition this review examines currently available medications and developing pharmacological therapies that hold significant promise in the treatment of arthrofibrosis.