Intraarticular microbial DNA as a novel mediator of osteoarthritis

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Project Summary / Abstract The objective of the proposed research is to better understand how cartilage microbial DNA patterns are established, and how these relate to osteoarthritis (OA) pathogenesis and progression. Previously published studies have outlined both gut microbiome pro-inflammatory changes with aging generally, but no work has yet been performed to examine how the gut and/or cartilage microbiomes, inflammation, and epigenetics intersect with OA. Our laboratory has previously examined in detail the epigenetic changes within cartilage and subchondral bone that are associated with OA development, and we have recently examined epigenetic changes within peripheral blood cells of human OA patients which are associated with increased risk of rapid OA progression. Our first Aim is to determine whether the cartilage microbial DNA pattern originates from the gut microbiome. To do this, we will populate the gut microbiome of germ-free mice with microbiota from young and OA-susceptible C57BL6/J (B6) mice then determine cartilage microbial DNA patterns at prespecified timepoints following inoculation. If successful, we will go on to test how variations in the cecal microbiome, associated with OA risk factors including aging and obesity, are reflected in changes of the cartilage microbiome profile. Furthermore, we will determine whether already-established cartilage microbiome patterns can be altered via changing the gut microbiome. Our second Aim will determine whether cartilage microbial DNA is sufficient to change the risk for OA development in mice. To do this, we will inject microbial DNA amplified from human OA patients and healthy controls into the knee joints of germ-free mice, then induce OA by disruption of the medial meniscus (DMM) surgery and measure histopathological outcome. If successful, we will then go on to determine local and systemic inflammatory cell population changes by CyTOF, serum cytokine changes by Bioplex assay, and epigenetic and transcriptomic changes on a genome-wide level following intraarticular microbial DNA delivery. The proposed work is important, as we do not have a full understanding of how non-genetic OA risk factors increases OA risk, nor do we understand how the microbiome influences OA risk. Our work is quite innovative in its use of germ-free mouse microbiome transplantation to evaluate OA and the use of cutting-edge CyTOF and epigenetic analyses. Finally, we will be the first to evaluate whether gut microbiome transplantation may be used as a therapeutic agent to prevent OA. Success in our proposal may open a new avenue for OA aging research and may offer a novel treatment strategy for OA.