Functional impairment in tendons, such as those which control movement in the heel, elbow and shoulder represents a major health care problem. It is now widely believed that tendon overuse, as seen in sports (tennis elbow) or work related (carpal tunnel) activities, is the initiating factor for development of tendinopathy. This appears to be true, at least for the expanding number of patients in the vulnerable 30-50 year age group. A pathogenic pathway, favored by most in the field, is that overuse results in persistent micro- injury of tendon collagen fibers and that this wounding precipitates a series o cellular responses which result in further loss of tissue material properties and chronic pain. Our long-term goal is to determine whether the aberrant cell responses which accompany tendinopathies, can be redirected from degeneration to healing by the application of tailored biologic and/or biomechanical therapies. We are optimistic about a successful outcome of our studies since we believe that we have uncovered a central pathogenic pathway to tendinopathy which we anticipate will be amenable to such therapeutic control. The pathogenic pathway involves the accumulation of deposits we term ARDs, or aggrecan-rich deposits in the tendon matrix. This pathway has emerged from studies on equine tendinopathy in a susceptible breed of horses. We are pursuing mechanistic studies in wild type and ADAMTS5-deficient mice which exhibit tendon changes (biomechanical and biochemical) that mimic the human pathology. The mechanistic pathway under study suggests that both mechanical loading (exercise) and ADAMTS5 pathway activation are required to eliminate the ARDs (pericellular aggrecan accumulation). We are working on therapeutic approaches to eliminate these deposits via different mechanical loading modes (eccentric versus concentric exercise) as well as by direct injection of aggrecanolytic agents. Furthermore, we will directly apply the knowledge gained from these murine studies in order to examine the efficacy of mechanobiologic strategies to treat human tendinopathic tissues.
Agents which can be used to effectively treat chronic human tendinopathy have not yet been developed, although there are now some promising candidates, such as recombinant human platelet-derived growth factor. Such medications should slow tendon degeneration, reduce pain, and improve mobility. Our research aims to reveal mechanobiological mechanisms by which physiotherapy - independently or in combination with new biologic agents - can function to achieve these therapeutic goals. We predict that a detailed understanding of this mechanism will translate into changes in clinical practice which will directl benefit the increasing population of individuals with pathologic heel, elbow and shoulder tendons.
| Sikes, Katie J; Li, Jun; Gao, Shu-Guang et al. (2018) TGF-b1 or hypoxia enhance glucose metabolism and lactate production via HIF1A signaling in tendon cells. Connect Tissue Res 59:458-471 |
| Sikes, Katie J; Renner, Kristen; Li, Jun et al. (2018) Knockout of hyaluronan synthase 1, but not 3, impairs formation of the retrocalcaneal bursa. J Orthop Res 36:2622-2632 |
| Trella, Katie J; Li, Jun; Stylianou, Eleni et al. (2017) Genome-wide analysis identifies differential promoter methylation of Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12 in murine tendinopathy. J Orthop Res 35:947-955 |
| Sayegh, Eli T; Sandy, John D; Virk, Mandeep S et al. (2015) Recent Scientific Advances Towards the Development of Tendon Healing Strategies. Curr Tissue Eng 4:128-143 |
