In an effort to elucidate the interplay between mechanical load and proteolytic gene expression in arthritic tissue degradation, we investigated cellular morphology and mRNA levels of matrix metalloproteinase-13 (MMP-13) genes under mechanical stress in human MH7A synovial cells. The cells were isolated from the knee joint of a rheumatoid arthritis patient. Using a reverse transcription-polymerase chain reaction procedure, we found that loading by an oscillatory shaker transiently decreased the level of MMP-13 mRNA and unloading by a clinostat increased its mRNA level. The unloaded cells appeared to be rounded and displayed a poorly developed track of peripheral fibers, whereas the cells under loading tended to align to the shear flow and were elongated. We also found that altering the oscillatory direction of mechanical loads contributed to a further reduction in mRNA expression of MMP-13. Our results demonstrate the role of mechanical loading and unloading in the transcriptional regulation of MMP-13 in synovial cells, and suggest the potential value of physical therapy for arthritic joints.