Rheumatoid arthritis, a chronic inflammatory disease, is characterised by the proliferation of synovial cells, a process that ultimately leads to the destruction of the underlying cartilage and bone. Such synovial expansion is dependent on an adequate blood supply, and angiogenesis has been implicated in the development of rheumatoid arthritis. Inhibiting the development of new blood vessels could therefore prove effective in blocking disease progression.
Hepatocyte growth factor (HGF) is known to be a potent angiogenic factor that stimulates endothelial cell growth. Studies have already shown that inhibiting HGF signalling may help prevent tumour metastasis. Hajime Sano, of Hyogo College of Medicine, Japan, and colleagues therefore investigated whether HGF inhibition may be similarly beneficial in preventing disease progression in a mouse model of rheumatoid arthritis, as reported in their recent study in Arthritis Research & Therapy.
Using an adenovirus expressing the gene for the HGF antagonist NK4 (AdCMV.NK4), they assessed the effects of blocking HGF on joint swelling and histopathologic changes in β-glucan induced arthritis in SKG mice – an established genetic model for rheumatoid arthritis. An adenovirus carrying the LacZ gene (AdCMV.LacZ) was used as the control. To assess the preventive and therapeutic effects of the treatment, AdCMV.NK4 and the control were administered intravenously at the time of β-glucan injection and 1 month after the injection, respectively. In both experiments mice that received AdCMV.NK4 had less joint swelling (as determined by the clinical score and ankle volume) 60 days after β-glucan injection compared with those that received the control.
The results of the histopathological and x-ray examinations of the ankle joints supported these findings. AdCMV.LacZ treated mice showed vigorous proliferation of synovial cells as well as erosion of the cartilage and subchondral bone, whereas AdCMV.NK4 treatment suppressed both of these events. Finally, synovial tissues from AdCMV.LacZ treated mice were found to express high levels of the cytokines IL-1, IL-6 and TNF-α, but mice given AdCMV.NK4 did not express these cytokines.
Systemic administration of NK4 to block HGF activity is therefore able to both inhibit the proliferation of synovial cells and reduce inflammatory responses in the ankle joints of SKG mice. These findings, albeit only in an animal model thus far, suggest a promising role for HGF inhibition by NK4 in the treatment of rheumatoid arthritis.