Osteoarthritis (OA) and rheumatoid arthritis (RA) are widespread disabling joint disorders that are considered to be polygenic in nature. This study investigated the spatial expression patterns of all six known human CCN genes using end-stage OA and RA joint samples. We performed in situ hybridization and histological analysis to investigate the spatial expression patterns of human CCN genes using joint tissues obtained during total knee and hip joint replacement procedures on patients with advanced OA or RA. Normal joint tissues taken while performing bipolar hip replacement surgeries were used as controls. All CCN genes were expressed at higher levels in OA and RA synovial samples as compared with normal controls. Whereas CCN3 and CCN6 were undetectable in control, OA, and RA cartilage, CCN1, CCN2, CCN4, and CCN5 were expressed to a greater extent in OA and RA knee cartilage. Our results indicate an involvement of several CCN genes in the pathophysiology of OA and RA.