Objective. Chronological age is a powerful epidemiologic risk factor for osteoarthritis (OA), a multifactorial disease that is characterized by articular cartilage (AC) degradation. It is unclear from a molecular perspective how aging interacts with OA to produce this risk to AC integrity. To address this key question, we used in vivo time-course analysis of OA development and murine interstrain variability in natural susceptibility to OA to examine changes in non-OA-prone CBA mice versus OA-prone STR/Ort mice, which develop disease that bears significant histologic resemblance to human OA. Through global transcriptome profiling, we attempted to discover the molecular signature linked with both OA vulnerability and progression.Methods. Affymetrix Mouse Gene 1.0 ST Array profiles were generated from AC samples derived from CBA and STR/Ort mice at 3 different ages, corresponding to the stages prior to, at, and late after the natural onset of OA in the STR/Ort mice.Results. We found that the OA in STR/Ort mice exhibited a molecular phenotype resembling human OA, and we pinpointed a central role of NF-B signaling and the emergence of an immune-related signature in OA cartilage over time. We discovered that, strikingly, young healthy AC has a highly expressed skeletal muscle gene expression program, which is switched off during maturation, but is intriguingly retained in AC during OA development in STR/Ort mice.Conclusion. This study is the first to show that AC chondrocytes share a high-abundance gene-expression program with skeletal muscle. We show that failure to switch this program off, as well as the restoration of this program, is associated with inappropriate expression of NF-B signaling pathways, skeletal musclerelated genes, and induction and/or progression of OA.Osteoarthritis (OA) is a complex age-related, multifactorial, polygenic disease characterized by degradation and consequent loss of the extracellular matrix (ECM) of the articular cartilage (AC) (1). Chondrocytes, the only resident cells of AC, are vital for maintaining the integrity of normal joints, but they also contribute to the initiation and progression of the loss of AC in OA (2,3). These dual roles in healthy ECM remodeling and in pathologic changes in the AC have made it difficult to identify targets by which to limit OA development or protect against increased susceptibility during aging.The study of OA currently relies upon in vivo animal models, partly because it is difficult to obtain AC samples during specific stages of OA in humans, as well as healthy site-and age-matched samples for comparison. Preclinical models of OA are also needed for drug development (4). Alternative comparative approaches in humans have relied mostly upon using normal AC samples and samples obtained during late-stage OA or