Principal Investigator: Aimee Colbath

DESCRIPTION (provided by applicant): 

Mast cells are few but powerful cells with potent inflammatory effects. Although largely overlooked in osteoarthritis (OA) research, our group has produced preliminary data suggesting their importance in OA. Mast cells live months to years in the tissues and proliferate locally. These cells have a potent inflammatory effect which can result in tissue destruction through mediators such as histamine and tryptases. Our preliminary data in mice confirm a pro-inflammatory effect of mast cells with a significant decrease in tissue destruction in mast-cell deficient mice. Mast cells are activated by interleukin-1 (IL-1β), a common cytokine in OA. Further, some evidence exists that histamine receptor antagonists may reduce the severity of OA in mouse models. However, the effects of activated mast cells on cells within the joint, including synoviocytes and chondrocytes, is still unknown. The overall aim of this work is to determine the effect of activated mast cells on equine joint tissues. In order to determine this, we will initially evaluate the response of equine mast cells to IL-1β. Then we will determine the effect of these activated mast cells on synoviocytes and chondrocytes in vitro. We will quantify the release of inflammatory mediators by synoviocytes and chondrocytes and evaluate the upregulation of inflammatory genes. We hypothesize that equine mast cells subjected to IL-1β will cause production of inflammatory mediators and upregulation of inflammatory genes by chondrocytes and synoviocytes. Subsequently, we will evaluate the effects of mast cells on ex-vivo cartilage explants where chondrocytes are protected by extracellular matrix. Cartilage health will be assessed using assays to evaluate cell death and proteoglycan content. We hypothesize that exposure of cartilage to inflammatory mast cells will result in significant cartilage destruction. This work will provide exciting preliminary data for novel osteoarthritis treatment targets in racehorses. Mast cell associated therapies, including targeted antihistamines, are prevalent and inexpensive. The possibility of repurposing these medications is potentially attractive when designing OA treatment interventions. The data will be used for future grant applications including pursuing funding from the Grayson Jockey Club Foundation. It is anticipated that future investigations will include targeted therapeutic interventions.