The purpose of this work is to determine the relationship between biomarkers of inflammation, structure, and pain with radiographic disc space narrowing (DSN) in community-based participants. A total of 74 participants (37 cases and 37 controls) enrolled in the Johnston County Osteoarthritis (OA) Project during 2006-2010 were selected. Cases had at least mild radiographic DSN and low back pain (LBP). Controls had neither radiographic evidence of DSN nor LBP. Measured analytes from human serum included N-cadherin, Keratin-19, Lumican, CXCL6, RANTES, IL-17, IL-6, BDNF, OPG and NPY. A standard dolorimeter measured pressure-pain threshold. Coefficients of variation (CVs) were used to evaluate inter- and intra-assay reliability. Participants with similar biomarker profiles were grouped together using cluster analysis. Binomial regression models were used to estimate risk ratios (RR) and 95% confidence intervals (CI) in propensity score matched models. Significant associations were found between radiographic DSN and OPG (RR=3.90 95% CI 1.83, 8.31), IL-6 (RR=2.54 95% CI 1.92, 3.36) and NPY (RR=2.06 95% CI 1.62, 2.63). Relative to a cluster with low levels of biomarkers, a cluster representing elevated levels of OPG, RANTES, Lumican, Keratin-19 and NPY (RR=3.04 95% CI 1.22, 7.54) and a cluster representing elevated levels of NPY (RR=2.91 95% CI 1.15, 7.39) were significantly associated with radiographic DSN. Clinical Significance: These findings suggest that individual and combinations of biochemical biomarkers may reflect radiographic DSN. This is just one step towards understanding the relationships between biochemical biomarkers and DSN that may lead to improved intervention delivery. This article is protected by copyright. All rights reserved.