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Updated: Jun 8, 2026
Oropharyngeal Administration of Bleomycin in the Murine Model of Pulmonary Fibrosis
Published on: May 9, 2025
CCN2 is required for bleomycin-induced skin fibrosis in mice
Shangxi Liu1, Xu Shi-wen, David J Abraham
1Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
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.
Insights
Connective tissue growth factor CCN2 is crucial for skin fibrosis development. Mice lacking CCN2 in smooth muscle cells/fibroblasts resisted bleomycin-induced skin scleroderma, suggesting CCN2 as a therapeutic target.
Area of Science:
- Connective tissue biology
- Fibrosis research
- Dermatology
Background:
- Connective tissue growth factor (CCN2) is a matricellular protein associated with fibrotic diseases.
- The precise role of CCN2 in fibrogenesis remains incompletely understood.
- Currently, no effective therapies exist for fibrotic conditions.
Purpose of the Study:
- To investigate the role of CCN2 in fibrogenesis.
- To determine if mice with a fibroblast/smooth muscle cell-specific deletion of CCN2 are resistant to bleomycin-induced skin scleroderma.
Main Methods:
- Cutaneous fibrosis was induced in mice using bleomycin injections.
- Mice with a fibroblast/smooth muscle cell-specific deletion of CCN2 were analyzed for fibrotic changes.
- Dermal fibroblasts were isolated to assess responses to transforming growth factor beta (TGFβ).
Main Results:
- CCN2 deficiency conferred resistance to bleomycin-induced skin fibrosis.
- CCN2-deficient mice lacked myofibroblasts in fibrotic lesions compared to wild-type mice.
- Fibroblast responses to TGFβ were not impaired, suggesting CCN2's role in myofibroblast recruitment.
Conclusions:
- CCN2 is essential for the development of bleomycin-induced skin fibrosis.
- Therapeutic strategies targeting CCN2 may offer a novel approach for treating fibrotic skin diseases.
