Arthrofibrosis is a very prevalent debilitating complication of routine total knee arthroplasty. Our laboratory develops mechanism-based strategies for (i) treatment of arthrofibrosis, (ii) early intervention when the disease process is initiated, and (iii) identification of novel biomarkers that permit the monitoring of disease progression. We will address a major knowledge gap by addressing the central hypothesis that arthrofibrosis is initiated in vivo by local alterations in inflammation-related tissue repair processes after joint surgery. We propose that inflammatory processes modulate formation of mechano-protective transient connective tissues and that deregulation of normal joint tissue healing results in alterations in the growth, differentiation and activity of (proto)myofibroblasts that may emerge from the perivascular compartment of synovial tissues. To understand the mechanisms contributing to arthrofibrosis, we will analyze (i) the pathologic roles of inflammatory processes in a rabbit model for arthrofibrosis (Aim 1); and (ii) mechanisms of myofibroblastogenesis that are deregulated during arthrofibrosis by molecular analyses of biopsies and primary cell cultures from patients undergoing revision TKAs for arthrofibrosis, as well as established in vitro models for myofibroblast proliferation and differentiation in culture, as well as co-culture models with mast cells involved in the initial inflammatory response during tissue repair (Aim 2). The key deliverables of this proposal are translational innovation (Aim 1) by establishing (i) the mechanistic role of inflammation in arthrofibrosis and (ii) characterization of the potential efficacy of anti-inflammatory drugs to mitigate or reverse disease progression. Furthermore, this study is conceptually innovative (Aim 2) by establishing (iii) cell structure-linked kinase-mediated signaling pathways and gene regulatory networks that mediate myofibroblast differentiation in joint tissues, and (iv) functional consequences of inhibiting key regulatory proteins that drive the intrinsic ability of fibroblasts to convert to myofibroblasts.
Arthrofibrosis occurs frequently as a result of knee replacement procedures, but the reasons for joint stiffening have not been sufficiently explored, even though much progress has been made on fibrosis in non- musculoskeletal tissues (e.g., lung, kidney, heart). Our work will investigate two major ideas related to the formation of the extensive build-up of connective tissue that occurs during joint stiffening. First, we are considering the role of the immune system and inflammation-related mechanisms that are activated within two weeks of joint injury (e.g., due to surgery or trauma). This concept will be tested in a live rabbit model in which we treat animals with non-steroidal anti-inflammatory drugs (NSAIDs) during progression of arthrofibrosis. Second, we are investigating the idea that joint stiffening is in part linked to defects in the growth, differentiation and activity of tissue repair cells that may be recruited from adult mesenchymal stem cells residing around blood vessels and that interact with inflammation-related cells. These studies will uncover new fibrosis-related molecular pathways that could support new mechanism-based pharmacological therapies for arthrofibrosis. The main achievements of this study are biomedically relevant, because there is currently no approved effective pharmacological therapy to either prevent or treat joint stiffening. Furthermore, our studies move the boundary of knowledge by generating a highly detailed molecular blueprint of how repair cells can become error-prone in their responses to the physiological environment of the healing joint.
