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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

Expression of CCN5 and CCN2 in scar tissues after laminectomy. To determine the expression levels of CCN5 and CCN2, 24 healthy male Lewis rats (12 weeks old) were subjected to laminectomy. Then, the scar and surrounding normal tissues were collected. The expression levels of CCN5 and CCN2 were detected by RT-PCR (A). The corresponding protein levels were also evaluated by western blotting (B). *P<0.05 vs. normal tissues.
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f1-ijmm-36-01-0123: Expression of CCN5 and CCN2 in scar tissues after laminectomy. To determine the expression levels of CCN5 and CCN2, 24 healthy male Lewis rats (12 weeks old) were subjected to laminectomy. Then, the scar and surrounding normal tissues were collected. The expression levels of CCN5 and CCN2 were detected by RT-PCR (A). The corresponding protein levels were also evaluated by western blotting (B). *P<0.05 vs. normal tissues.

Mentions: CCN5 exerted an opposing function in CCN2-induced cardiac hypertrophy and fibrosis (14). However, its roles in scar-triggered epidural fibrosis remain to be determined. Laminectomized rats were used to determine the expression levels of CCN5 and CCN2 in scar tissue after laminectomy. RT-PCR analysis confirmed an obvious upregulation of CCN2 in scar tissues as compared to the surrounding normal tissues (Fig. 1A). A similar upregulation in CCN2 protein levels was demonstrated by western blotting (Fig. 1B). However, CCN5 expression levels were significantly downregulated during scar formation following laminectomy. CCN2 has been believed to act as a positive regulator of fibrogenesis, scar formation and wound repair (11). Therefore, these results suggest that CCN5 elicits potential anti-fibrotic effects during the development of scar formation based on opposing expression levels to CCN2 in scar tissues.


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)

Expression of CCN5 and CCN2 in scar tissues after laminectomy. To determine the expression levels of CCN5 and CCN2, 24 healthy male Lewis rats (12 weeks old) were subjected to laminectomy. Then, the scar and surrounding normal tissues were collected. The expression levels of CCN5 and CCN2 were detected by RT-PCR (A). The corresponding protein levels were also evaluated by western blotting (B). *P<0.05 vs. normal tissues.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijmm-36-01-0123: Expression of CCN5 and CCN2 in scar tissues after laminectomy. To determine the expression levels of CCN5 and CCN2, 24 healthy male Lewis rats (12 weeks old) were subjected to laminectomy. Then, the scar and surrounding normal tissues were collected. The expression levels of CCN5 and CCN2 were detected by RT-PCR (A). The corresponding protein levels were also evaluated by western blotting (B). *P<0.05 vs. normal tissues.
Mentions: CCN5 exerted an opposing function in CCN2-induced cardiac hypertrophy and fibrosis (14). However, its roles in scar-triggered epidural fibrosis remain to be determined. Laminectomized rats were used to determine the expression levels of CCN5 and CCN2 in scar tissue after laminectomy. RT-PCR analysis confirmed an obvious upregulation of CCN2 in scar tissues as compared to the surrounding normal tissues (Fig. 1A). A similar upregulation in CCN2 protein levels was demonstrated by western blotting (Fig. 1B). However, CCN5 expression levels were significantly downregulated during scar formation following laminectomy. CCN2 has been believed to act as a positive regulator of fibrogenesis, scar formation and wound repair (11). Therefore, these results suggest that CCN5 elicits potential anti-fibrotic effects during the development of scar formation based on opposing expression levels to CCN2 in scar tissues.

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