Purpose: Facet joint osteoarthritis (FJOA) is widely prevalent in middle-aged and older populations and is thought to be a common cause of back pain. The etiopathogenesis of FJ OA remains unclear. NFAT1 (NFATc2) is a member of the family of nuclear factor of activated T cells (NFAT/Nfat) transcription factors. Previous studies revealed that mice with a global deletion of the Nfat1 gene displayed osteoarthritic changes in appendicular synovial joints. However, whether NFAT1 deficiency affects synovial joints of the spine remains unknown. This study aimed to test our hypothesis that NFAT1 deficiency causes FJOA in mice because NFAT1 is essential for maintaining homeostasis of articular cartilage and synovium of the facet joints. Methods: Lumbar spine tissue samples were harvested from Nfat1 knockout (Nfat1-/-) mice and wild-type (WT) mice as negative controls at the age of 2, 6, and 12 months for histopathological and molecular biological analyses. L3-S1 lumbar spine samples were fixed in 2% paraformaldehyde. Tissue sections prepared with decalcification and embedded in paraffin were used for safranin-O and fast green staining to identify cartilage cells and matrices. Hematoxylin and Eosin (H&E) staining was performed for structural/cellular analysis of bone and soft tissues. Total RNA isolated from articular cartilage and synovium (with a thin layer of fibrous capsular tissue) of L3-S1 facet joints were reverse-transcribed for gene expression analysis using quantitative real-time RT-PCR (qPCR). All animal procedures were approved by the Institutional Animal Care and Use Committee. Statistical analyses were performed with the Student t-test and ANOVA. Results: At 2 months of age, the intensity of safranin-O staining (for proteoglycans) in articular cartilage of the lumbar facet joints was substantially reduced in Nfat1-/- mice, compared to that of the WT mice. OA-like structural changes (e.g. articular surface fibrillations/clefts and osteophyte formation) were not evident. At 6 months, mild to moderate OA structural changes occurred in the lumbar facet joints of Nfat1-/- mice, but not in WT mice. At 12 months, severe OA structural changes were observed in the lumbar facet joints of Nfat1-/- mice, but not in WT mice. Subchondral bone changes were not remarkable in the Nfat1-/- facet joints at any time points. qPCR gene expression analysis demonstrated significantly decreased expression of mRNA for aggrecan (Acan) with significantly increased expression of mRNA for interleukin-1β (Il1b) in the Nfat1-/- facet joint cartilage at 2 months. Significantly decreased expression of mRNA for collagen-II (Col2a1) and significantly increased expression of mRNAs for collagen-10, matrix metalloproteinase-3 (Mmp3), a disintegrin and metalloproteinase with thrombospondin motifs-5 (Adamts5), Il1b, and β-catenin (Ctnnb1) was detected in the Nfat1-/- facet joint cartilage at 6 and 12 months. Gene expression analysis of the synovial-capsular tissues revealed significantly increased Tnfa mRNA at 2 months and significantly increased Mmp3 and Adamts5 at 6 and 12 months. No sex differences were identified in the histological or gene expression analyses. Conclusions: The present study demonstrated for the first time that NFAT1 deficiency causes severe FJOA in mice. FJOA in the Nfat1-deficient mouse model initiates with increased expression of proinflammatory cytokines in articular cartilage and synovium, suggesting that inflammation may play an important role in the initiation stage of NFAT1 deficiency-induced FJOA in mice. These results support our hypothesis that NFAT1 deficiency causes FJOA through dysfunction of both articular chondrocytes and synovial cells.