Spatial Proteomics of osteoarthritis in bones to uncover disease progression - PROJECT SUMMARY / ABSTRACT There is an urgent need to develop novel and innovative technologies to advance health and therapeutic interventions and to develop tools for monitoring of disease progression in the musculoskeletal system. Molecular details of disease and injury of the musculoskeletal system are particularly needed for novel proteomic assays to monitor disease progression in osteoarthritis or meniscal injury. Our innovative approach includes development of Mass Spectrometry Imaging (MSI) technologies for joints to spatially visualize proteins of the extracellular matrix (ECM) and glycans, and to apply deep proteomic profiling of bones. These technologically novel approaches will also enable us to develop urgently needed molecular assays to assess the efficacy of interventions. Molecular changes related to age, injury or osteoarthritis (OA) in musculoskeletal tissues, particularly bone and cartilage, are typically spatially distinct. This is even more evident when considering temporal and dynamic changes during emerging functional decline. Our national team provides a unique combination of expertise to develop new, innovative and paradigm-changing tools to investigate bone diseases, such as OA, age-related changes in bone, and changes induced by injury to meniscus. Dr. Schilling (Buck Institute) is an expert in proteomics, global bone analysis, senescence and aging, Dr. Alliston (UC San Francisco) is an expert in orthopedics, bone mechano-biology, and osteoarthritis disease biology, and Dr. Angel (Medical University of South Carolina, MUSC) is an expert in MSI, spatial ECM proteomics, and glycan biology. We will employ and optimize state-of-the-art mass spectrometry imaging (MSI) technologies to spatially resolve molecular changes in tissues (using a molecular readout mass/charge: m/z) in human and mouse tissue slices monitoring hundreds of analytes simultaneously. These innovative technologies indicate premise to develop into groundbreaking tools for the orthopedic and musculoskeletal community to investigate bone and cartilage decline, and to monitor interventive treatments. With this paradigm change, we will be able to image hundreds or even thousands of molecules simultaneously at 15 to 40 µm spatial resolution. Protein signatures from the extracellular matrix in human OA knee tissues revealed very advanced disease progression in cartilage and bone at the inner (medial) side of the knee (with healthier tissue at the outer/lateral side) discovering distinct novel OA protein targets. These results and novel spatial assays, in combination with deep proteomic profiling of the bone proteome (>2,000 protein groups), will provide insights into disease mechanisms and allow for unbiased proteomic monitoring during functional decline of joints and bones. Robust statistical processing is implemented. As individual lifespans increase across the world, age-related complications are increasing and develop into a major public health challenge. The unique MS Imaging and Proteome Profiling capabilities of our team provide major opportunities for the discovery of Novel Disease Targets for therapeutic interventions.
