Objective
No therapy for fibrotic disease is available. The proadhesive matricellular protein connective tissue growth factor CCN2 is a marker of fibrotic cells; however, the specific role of CCN2 in connective tissue biology in general and in fibrogenesis in particular is unclear. The aim of this study was to assess whether adult mice bearing a smooth muscle cell/fibroblast–specific deletion of CCN2 are resistant to bleomycin‐induced skin scleroderma.
Methods
Cutaneous fibrosis was induced in mice by subcutaneous injection of bleomycin. Untreated control groups were injected with phosphate buffered saline. Mice bearing a fibroblast/smooth muscle cell–specific deletion of CCN2 were investigated for changes in dermal thickness, collagen content, and the number of α‐smooth muscle actin (α‐SMA)–positive cells. Dermal fibroblasts were isolated to assess whether the induction of collagen and α‐SMA messenger RNA in response to transforming growth factor β (TGFβ) was impaired.
Results
The loss of CCN2 resulted in resistance to bleomycin‐induced skin fibrosis. In response to bleomycin, wild‐type mice possessed, but CCN2‐deficient mice lacked, abundant α‐SMA–expressing myofibroblasts within fibrotic lesions. Fibroblast responses to TGFβ, a potent inducer of myofibroblast differentiation, were not affected. Collectively, these results indicate that CCN2 is essential for bleomycin‐induced skin fibrosis, likely due to a defect in myofibroblast recruitment.
Conclusion
These data indicate that therapeutic strategies that involve blocking CCN2 in vivo may be of benefit in combating fibrotic skin disease.