The objective of this grant application 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, funded for the past year under the OA Biomarkers Network, indicates that PBL derived from a subset OA patients exhibit a """"""""cytokine activation profile"""""""", suggesting leukocyte exposure to stimuli during the course of perfusion of diseases joint tissues. To pursue these findings, the grant will have three central aims:
In Specific Aim 1 we 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 3 cohorts, overall and pairwise 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 stage OA. We will validate PBL gene expression profiles of knee OA in an independent population, the Duke knee OA cohort, in collaboration with Dr. Virginia Kraus.
In Specific Aim 2 we will examine the association of PBL gene expression profiles with findings on MRI and bone scintigraphy. We will perform MRI studies using a clinical 3.0 T MRI system on 180 patients at NYU-HJD, who will be entered into a two year longitudinal cohort study. We will perform semiquantitative analyses of articular cartilage integrity, subchondral marrow lesions, synovitis/effusion, marginal osteophytes, assessing both global and individual compartment scores. In collaboration with Dr. Kraus we 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. We 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 2 year longitudinal to determine whether specific PBL gene expression patterns predict OA disease progression. We 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: i) clinical evaluation including BMI determination, ii) pain and function assessment (complete WOMAC), iii) serum COMP. In addition, serum, plasma and urine will be collected for future biomarker determinations. We anticipate that these studies will enhance our understanding of the pathogenesis of OA and provide a combinatorial biomarker that may predict OA disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052873-06
Application #
7649322
Study Section
Special Emphasis Panel (ZRG1-MOSS-J (02))
Program Officer
Tyree, Bernadette
Project Start
2005-08-20
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2012-07-31
Support Year
6
Fiscal Year
2009
Total Cost
$306,642
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Krasnokutsky, Svetlana; Oshinsky, Charles; Attur, Mukundan et al. (2017) Serum Urate Levels Predict Joint Space Narrowing in Non-Gout Patients With Medial Knee Osteoarthritis. Arthritis Rheumatol 69:1213-1220
Jain, Manish; Attur, Mukundan; Furer, Vika et al. (2015) Increased plasma IL-17F levels in rheumatoid arthritis patients are responsive to methotrexate, anti-TNF, and T cell costimulatory modulation. Inflammation 38:180-6
Attur, M; Statnikov, A; Samuels, J et al. (2015) Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis. Osteoarthritis Cartilage 23:1915-24
Attur, Mukundan; Krasnokutsky, Svetlana; Statnikov, Alexander et al. (2015) Low-grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers. Arthritis Rheumatol 67:2905-15
Raya, José G; Dettmann, Eike; Notohamiprodjo, Mike et al. (2014) Feasibility of in vivo diffusion tensor imaging of articular cartilage with coverage of all cartilage regions. Eur Radiol 24:1700-6
Wisniewski, H-G; Colón, E; Liublinska, V et al. (2014) TSG-6 activity as a novel biomarker of progression in knee osteoarthritis. Osteoarthritis Cartilage 22:235-41
Kennish, Lauren; Attur, Mukundan; Oh, Cheongeun et al. (2014) Age-dependent ferritin elevations and HFE C282Y mutation as risk factors for symptomatic knee osteoarthritis in males: a longitudinal cohort study. BMC Musculoskelet Disord 15:8
Hochberg, Marc C; Yerges-Armstrong, Laura; Yau, Michelle et al. (2013) Genetic epidemiology of osteoarthritis: recent developments and future directions. Curr Opin Rheumatol 25:192-7
Attur, Mukundan; Krasnokutsky-Samuels, Svetlana; Samuels, Jonathan et al. (2013) Prognostic biomarkers in osteoarthritis. Curr Opin Rheumatol 25:136-44
Wang, Ligong; Salibi, Nouha; Chang, Gregory et al. (2012) Assessment of subchondral bone marrow lipids in healthy controls and mild osteoarthritis patients at 3T. NMR Biomed 25:545-55

Showing the most recent 10 out of 17 publications