Liu Shangxi, Shi-wen Xu, Abraham David J, Leask Andrew
Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Arthritis Rheum. 2011 Jan;63(1):239-46. doi: 10.1002/art.30074.
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.
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.
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.
These data indicate that therapeutic strategies that involve blocking CCN2 in vivo may be of benefit in combating fibrotic skin disease.
目前尚无针对纤维化疾病的治疗方法。促黏附基质细胞蛋白结缔组织生长因子CCN2是纤维化细胞的标志物；然而，CCN2在一般结缔组织生物学中，特别是在纤维生成中的具体作用尚不清楚。本研究的目的是评估成年小鼠平滑肌细胞/成纤维细胞特异性缺失CCN2是否对博来霉素诱导的皮肤硬皮病具有抗性。
通过皮下注射博来霉素在小鼠中诱导皮肤纤维化。未治疗的对照组注射磷酸盐缓冲盐水。对成纤维细胞/平滑肌细胞特异性缺失CCN2的小鼠进行真皮厚度、胶原蛋白含量和α平滑肌肌动蛋白（α-SMA）阳性细胞数量变化的研究。分离真皮成纤维细胞以评估对转化生长因子β（TGFβ）的反应中胶原蛋白和α-SMA信使核糖核酸的诱导是否受损。
CCN2的缺失导致对博来霉素诱导的皮肤纤维化具有抗性。对博来霉素的反应中，野生型小鼠在纤维化病变中有丰富的表达α-SMA的肌成纤维细胞，但CCN2缺陷型小鼠缺乏。成纤维细胞对TGFβ（肌成纤维细胞分化的有效诱导剂）的反应不受影响。总体而言，这些结果表明CCN2对博来霉素诱导的皮肤纤维化至关重要，可能是由于肌成纤维细胞募集缺陷所致。
这些数据表明，在体内阻断CCN2的治疗策略可能有助于对抗纤维化皮肤病。
