The prevalence of tendinopathy is increasing in the United States as the average age of the population and life expectancy increases. Tendinopathy occurs at various locations through the human body, including, the ankle, hip, knee, shoulder, elbow, wrist, and hand. This particular subset of disease accounts for about 30% of all musculoskeletal consultations. Despite a variety of treatment options for tendinopathy (pharmaceutics, rehabilitation, surgery, extracorporeal shockwave therapy), there are no therapies providing permanent relief. The long-term goal of this research is to understand the development of chronic tendinopathy and develop a clinical intervention to improve outcomes. The role of inflammation in tendinopathy has been widely debated in the last two decades, and still remains unclear. The specific goal of this project is to evaluate the role of inflammation in tendinopathy through the use of two unique tissue-specific transgenic mice. IKKB has been identified as a particular molecular target in the NF-KB signaling pathway that is critical to IL1?-induced inflammation. Cytokines such as IL-1? have been implicated in many tendinopathies and have detrimental effects on tendon fibroblasts. A tendon-specific inflammatory model was developed for this proposal that entails a knock-in of constitutive active IKKB (IKKBSSEE) into tendon fibroblasts by crossing mice carrying this floxed gene with mice expressing cre-recombinase under the tendon-specific scleraxis promoter. Conversely, tendon-specific deletion of wild type form of IKKB will be accomplished by crossing mice harboring floxed forms of these genes with scleraxis cre-recombinase mice.
The first aim of the study seeks to determine the effects of experimentally induced inflammatory environments on tendon fibroblasts isolated from the rotator cuff tendons from the aforementioned mice. The inflammatory in vitro environments will be achieved by: 1) exogenous addition of IL-1?, 2) co-culture with activated macrophages, and 3) cyclic loading.
The second aim utilizes an in vivo rotator cuff tendinopathy animal model and examines the necessity of IKKB for the development of the pathology. We hypothesize that deletion of IKKB in tendon fibroblasts will protect these cells from degeneration in both in vitro and in vivo models. The ability to knock in and delete key parts of the inflammation pathway in tendon fibroblasts and consequently evaluate their response to experimentally induced inflammatory environment may help identify specific molecular targets to prevent the progression of tendinopathies.
Tendinopathies are the most common musculoskeletal disease and the prevalence of tendinopathies is rising with the average age of the population and with life expectancy. Understanding the role of inflammation in tendinopathies will help identify treatments for these conditions. The proposed study may lead directly to specific molecular targets for pharmaceutical intervention, as selective inhibitors are available for the molecules being evaluated in this study.
|Manning, Cionne N; Martel, Catherine; Sakiyama-Elbert, Shelly E et al. (2015) Adipose-derived mesenchymal stromal cells modulate tendon fibroblast responses to macrophage-induced inflammation in vitro. Stem Cell Res Ther 6:74|