Project 2: Synovial Fluid Proteomics

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ABSTRACT Project 2: Synovial Fluid Proteomics (previously Project 4) Osteoarthritis (OA) is the most common form of arthritis and a leading cause of physical disability in older individuals. There are no approved pharmacologic treatments available beyond those for symptomatic relief and no biomarkers available to assess disease status or risk of progression. Major reasons for this may include key differences between blood and intra-articular biomarkers and the dominating influence of biomechanics that makes it difficult to differentiate systemic from mechanical contributions to OA. There may be differences between single-site knee and multi-site OA that occurs in hands and knees since the latter may result from systemic initiation rather than joint-specific factors. Assessment of proteins in joint-specific synovial fluid that is in direct contact with joint tissues and paired blood plasma may provide insights into joint-specific and systemic factors in OA. The proposed study will fill a gap in knowledge about the pathobiology of knee and multi-site OA. The objective of this proposal is to identify novel OA biology underlying knee and multi-site OA using proteomic analyses of paired synovial fluid and blood plasma. Our central hypothesis is that there are molecular signatures in synovial fluid and blood plasma that can be used to identify biomarkers for OA and which differentiate systemic from joint-specific molecular contributors to OA. Our long-term goal is to identify biomarkers that assess OA burden and disease progression and that provide insights into disease pathogenesis. We will assess returning participants from the Multicenter Osteoarthritis Study (MOST), a well-characterized prospective cohort of older individuals aged 54-86 years to assess risk factors for incidence and progression of knee OA. All participants will undergo radiographic assessments for hand and knee OA at MOST4 Visit 1. Synovial fluid will be collected in those who have at least 1 ml of synovial fluid present on knee ultrasound (~500 participants), which will include those with and without frequent knee pain. We will measure proteins in ~500 paired synovial fluid and blood plasma samples using SOMAScan, an aptamer-based proteomics assay that simultaneously detects ~7,000 proteins. Proteomic findings in MOST will be replicated in an international consortium, STEpUP OA, which includes ~1,800 individuals from 5 cohorts with proteomic profiling in synovial fluid and plasma. Aim 1 will identify proteins in knee OA synovial fluid and plasma associated cross-sectionally with knee pain and MRI-detected cartilage damage. Aim 2 will identify proteins in knee OA synovial fluid and plasma associated with longitudinal worsening of knee pain or MRI-detected cartilage damage over 24 months. Aim 3 will identify proteins in plasma associated with multi-site OA. The expected outcome of this proposal is identification of proteomic signatures that underlie OA pathogenesis. This will be the first and largest study of paired OA synovial fluid and plasma proteomics, which will likely provide novel insights into joint-specific and systemic contributions to OA pathophysiology needed to identify novel biomarkers and suggest new treatment strategies for OA.