CCN5 attenuates profibrotic phenotypes of fibroblasts through the Smad6-CCN2 pathway: Potential role in epidural ﬁbrosis

Xu,Honghai; Liu,Cong; Sun,Zhengming; Guo,Xiong; Zhang,Yuelin; Liu,Mengting; Li,Peng

doi:10.3892/ijmm.2015.2190

CCN5 attenuates profibrotic phenotypes of fibroblasts through the Smad6-CCN2 pathway: Potential role in epidural ﬁbrosis

Authors:
- Honghai Xu
- Cong Liu
- Zhengming Sun
- Xiong Guo
- Yuelin Zhang
- Mengting Liu
- Peng Li
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Affiliations: Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Xi'an Medical College, Xi'an, Shaanxi 710061, P.R. China, Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Neurosurgery, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: April 21, 2015 https://doi.org/10.3892/ijmm.2015.2190
Pages: 123-129
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Epidural ﬁbrosis is characterized by the development of dense and thick scar tissue adjacent to the dural mater and ranked as the major contributor for post-operative pain recurrence after laminectomy or discectomy. Recently, CCN5 exhibited an inhibitory effect on connective tissue growth factor (CTGF)/CCN2 (a critical regulator for fibrotic disease)‑mediated fibrogenesis. However, its function in epidural fibrosis and the underlying mechanisms involved remain to be determined. In this study, an obvious downregulation of CCN5 was observed in scar tissues from laminectomized rats, concomitant with a marked upregulation of CCN2, suggesting a potential negative regulatory role of CCN5 in fibrogenesis. Furthermore, CCN5 overexpression notably mitigated transforming growth factor‑β1-enhanced fibroblast viability and proliferation. Of note, CCN5 upregulation inhibited the switch of fibroblasts into myofibroblasts as its overexpression abrogated the expression of the myoﬁbroblast marker, α-smooth muscle actin (α-SMA). CCN5 upregulation also reduced an increase in collagen type I, α1 (COL1A1) and total collagen concentrations. Additionally, CCN5 overexpression decreased CCN2 expression and increased Smad6 phosphorylation. Mechanism analysis revealed that blocking Smad6 signaling significantly ameliorated the inhibitory effect of CCN5 on the CCN2 levels, accompanied by the reduction in cell proliferation and collagen production. These results confirm that CCN5 exerts an anti-fibrotic function by regulating the Smad6-CCN2 pathway, thereby indicating a potential approach for ameliorating epidural ﬁbrosis after laminectomy.

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