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

Xu H, Liu C, Sun Z, Guo X, Zhang Y, Liu M, Li P - Int. J. Mol. Med. (2015)

Bottom Line: CCN5 upregulation also reduced an increase in collagen type I, α1 (COL1A1) and total collagen concentrations.Additionally, CCN5 over-expression 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 over-expression 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.

No MeSH data available.


Related in: MedlinePlus

CCN5 overexpression attenuates CCN2 levels. Following transfection with the recombinant CCN5, the cells were stimulated with transforming growth factor-β (TGF-β1). The expression levels of CCN2 mRNA (A) and protein (B) were detected by RT-PCR and western blotting, respectively. *P<0.05.
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f5-ijmm-36-01-0123: CCN5 overexpression attenuates CCN2 levels. Following transfection with the recombinant CCN5, the cells were stimulated with transforming growth factor-β (TGF-β1). The expression levels of CCN2 mRNA (A) and protein (B) were detected by RT-PCR and western blotting, respectively. *P<0.05.

Mentions: CCN2 is overexpressed in tissue repair and human diseases characterized by excessive scarring and fibrosis allowing it to be induced by TGF-β1 thereby enhancing the progressive fibrotic response to scar tissue formation (11,19). Based on the opposing expression levels of CCN5 and CCN2 in scar tissues, we analyzed the correlation between CCN5 and CCN2 during the fibrotic process of fibroblasts. TGF-β1 treatment induced an obvious upregulation of CCN2 mRNA levels (Fig. 5A). Further assay showed that CCN5 expression significantly attenuated this increase in CCN2 mRNA from 4.59- to 2.45-fold. The protein levels of CCN2 were also decreased following LV-CCN5 treatment, compared with the TGF-β1-treated group (Fig. 5B). These data indicate that CCN5 may exert anti-fibrotic effects by inhibiting the activation of the CCN2 pathway.


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

Xu H, Liu C, Sun Z, Guo X, Zhang Y, Liu M, Li P - Int. J. Mol. Med. (2015)

CCN5 overexpression attenuates CCN2 levels. Following transfection with the recombinant CCN5, the cells were stimulated with transforming growth factor-β (TGF-β1). The expression levels of CCN2 mRNA (A) and protein (B) were detected by RT-PCR and western blotting, respectively. *P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494601&req=5

f5-ijmm-36-01-0123: CCN5 overexpression attenuates CCN2 levels. Following transfection with the recombinant CCN5, the cells were stimulated with transforming growth factor-β (TGF-β1). The expression levels of CCN2 mRNA (A) and protein (B) were detected by RT-PCR and western blotting, respectively. *P<0.05.
Mentions: CCN2 is overexpressed in tissue repair and human diseases characterized by excessive scarring and fibrosis allowing it to be induced by TGF-β1 thereby enhancing the progressive fibrotic response to scar tissue formation (11,19). Based on the opposing expression levels of CCN5 and CCN2 in scar tissues, we analyzed the correlation between CCN5 and CCN2 during the fibrotic process of fibroblasts. TGF-β1 treatment induced an obvious upregulation of CCN2 mRNA levels (Fig. 5A). Further assay showed that CCN5 expression significantly attenuated this increase in CCN2 mRNA from 4.59- to 2.45-fold. The protein levels of CCN2 were also decreased following LV-CCN5 treatment, compared with the TGF-β1-treated group (Fig. 5B). These data indicate that CCN5 may exert anti-fibrotic effects by inhibiting the activation of the CCN2 pathway.

Bottom Line: CCN5 upregulation also reduced an increase in collagen type I, α1 (COL1A1) and total collagen concentrations.Additionally, CCN5 over-expression 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 over-expression 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.

No MeSH data available.


Related in: MedlinePlus