LEUKOCYTE GENE EXPRESSION IN OSTEOARTHRITIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Osteoarthritis (OA) is a disease characterized by altered biomechanics, genetic susceptibility and hormonal influences. The disease process affects the entire joint structure, including cartilage, synovial membrane, subchondral bone, which are active sites of growth factor, cytokine, protease and inflammatory mediator production. Reliable biomarkers remain elusive in this disease. Recent studies in our laboratory revealed the unexpected and novel observation that peripheral blood leukocytes (PBMCs) in OA are activated. Using gene expression array, OA-PBMCs were shown to differentially express clusters of transcripts that were distinct from normal controls. Among the upregulated transcripts was COX-2; cytokine-induced production of PGE2 was 5-fold higher in OA-PBMCs than in normal. A cluster of 54 transcripts sensitive to pharmacological intervention (COX-2 specific inhibitors) could also be identified in OA-PBMCs. Independently, human OA affected cartilage showed a specific (proliferation/neoplastic) gene expression signature in OA, which differed from normal and RA cartilage. The objective of this study is to use genomic technology to identify a novel cluster of biomarkers expressed by peripheral blood leukocytes (PBL) that will be clinically useful in the identification of patients with tibio-femoral knee osteoarthritis (OA), and to identify those patients at risk for disease progression. Preliminary data indicates that PBL derived from a subset of OA patients exhibits a "cytokine activation profile", suggesting leukocyte exposure to stimuli during the course of perfusion of diseased joint tissues. To pursue this finding, this study will have three central aims: Specific aim 1 will determine whether PBL gene expression patterns distinguish early OA (OA-E, K-L grade 2), advanced OA (OA-A, K-L grade 3) and healthy controls as defined by semi-flexed, fluoroscopically-positioned knee radiographs. For these three cohorts, overall and pair-wise comparisons of PBL gene expression profiles will be analyzed in order to identify a distinctive profile which discriminates the following: 1) OA versus normal, and 2) early versus advanced OA. The investigators will validate PBL gene expression profiles of knee OA in an independent population, the Duke Knee OA Cohort, in collaboration with Dr. Virginia Kraus. Specific aim 2 will examine the association of PBL gene expression profiles with findings on MRI and bone scintigraphy. The investigators will perform MRI studies using a clinical 3.0T MRI system on 180 patients at NYU-HJD, who will be entered into a two-year longitudinal cohort study. The investigators will perform semi-quantitative analysis of articular cartilage integrity, subchondral narrow lesions, synovitis/effusion, marginal osteophytes, assessing both global and individual compartment scores. In collaboration with Dr. Kraus they will also examine the association of PBL-gene expression profiles with signal knee "synovitis" and with "total body OA burden," as defined by early and late phase semi-quantitative bone scintigraphy, respectively. They will develop a multivariate model of OA radiographic stage to determine the independent associations of PBL-gene expression profiles with other risk factors including BMI, COMP, bone scintigraphy and varus/valgus deformities. Specific aim 3 will be a two-year longitudinal to determine whether specific PBL gene expression patterns predict OA disease progression. The investigators will assess OA patients with progression and without progression, as determined by both MRI and semi-quantitative knee radiography. Imaging evaluations will occur at 0 and 24 months. In addition to MRI and X-ray, each subject will undergo: 1) clinical evaluation including BMI determination, 2) pain and function assessment (complete WOMAC), 3) serum COMP. In addition, serum, plasma and urine will be collected for future biomarker determinations. The investigators anticipate that these studies will enhance our understanding of the pathogenesis of OA and provide a combinatorial biomarker that may predict OA disease progression.