Ankle arthritis was induced by a single subcutaneous (s.c.) infection of 1×107 c.f.u. of the Streptococcus dysgalactiae subspecies equisimilis strain RE378, which was isolated from a patient suffering from multiple organ failure due to septicaemia, into both hind footpads of human CD46-expressing transgenic (Tg) mice. In contrast, in non-Tg mice, the incipient foot lesions (swelling and redness) resolved before arthritis developed. The number of viable bacteria in tissue samples and the arthritis frequency on days 3 and 28 after infection were higher in CD46 Tg mice than in non-Tg mice. The histopathological findings in the hind ankle sections of CD46 Tg mice showed the stimulation of osteoclast formation associated with inflammation of the synovial membrane and the development of aggressive granulation tissue (pannus). In addition, increased expression levels of interleukin (IL)-6, receptor activator of NF-κB ligand, IL-1β and tumour necrosis factor alpha were detected in the foot bones of CD46 Tg mice but not in those of non-Tg mice. These observations suggest that the s.c. infection with S. dysgalactiae subsp. equisimilis induced arthritis in the ankle joints of CD46 Tg mice as a consequence of the prolonged inflammation associated with focal bone loss.