Local Delivery of AdipoRon to Treat Arthrofibrosis - ABSTRACT Arthrofibrosis is a debilitating condition that limits joint motion and causes substantial pain. It is a common complication (~5%) following routine total knee arthroplasty (TKA) and its symptoms are often resistant to pharmacological treatments, physical therapy, and revision surgeries. While aberrant extracellular matrix generation is the primary manifestation, the cellular and molecular effectors that trigger and sustain arthrofibrosis have yet to be elucidated. As a result, there are no therapeutic interventions available to prevent or treat arthrofibrosis following TKA. It is thus critical to establish non-surgical preventive and therapeutic modalities for arthrofibrosis. The scientific premise of our study is that routine surgical trauma caused by index TKA alters the local cellular environment, leading to loss of adipocytes and adipokines that inhibit myofibroblastogenesis and the formation of excessive fibrotic tissue in the joint. This application will address the central hypothesis that activation of the adiponectin cascade suppresses myofibroblast-induced scar tissue formation in the knee. Our working model is that arthrofibrosis development is promoted by the local absence of the adipose-derived hormone adiponectin. Preliminary data from our group reveal that adiponectin expression is suppressed in arthrofibrotic knees and the synthetic adiponectin mimetic AdipoRon exhibits anti-arthrofibrotic properties in vitro and in vivo. Our studies will (i) assess whether local sustained release of AdipoRon can prevent the onset of arthrofibrosis in a pre-clinical rabbit model (Aim 1) and (ii) define the impact of adipogenic factors, including Adiponectin and its mimetic AdipoRon, on myofibrogenesis and decipher the mechanisms by which the adiponectin-axis counteracts myofibroblast differentiation (Aim 2). These studies are impactful as development of novel and non-surgical therapeutic measures that prevent and/or treat arthrofibrosis will reduce complex, unpredictable, painful, and costly revision TKAs. Our studies provide conceptual innovation as a pre-clinical model of arthrofibrosis will be used to test if local AdipoRon delivery in the knee can prevent disease onset. In addition, we will define the role of the adipogenic milieu and of adiponectin signaling activation on myofibroblast differentiation using primary human cell culture models. Overall, we aim to establish novel therapeutic approaches to combat the onset and progression of arthrofibrosis.
