title: CCN5 attenuates profibrotic phenotypes of fibroblasts through the Smad6-CCN2 pathway: Potential role in epidural ﬁbrosis.
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.
authors.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.
authors.forename: Honghai
authors.initials: H
authors.lastname: Xu
authors.affiliation: Xi'an Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.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.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Xi'an Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Mengting
authors.initials: M
authors.lastname: Liu
authors.affiliation: Xi'an Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000096:biosynthesis / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis / Q000473:pathology*; D007796:Laminectomy / Q000009:adverse effects; D008297:Male; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D011917:Rats, Inbred Lew; D012097:Repressor Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism*; D013131:Spine / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D055511:CCN Intercellular Signaling Proteins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051905:Smad6 Protein; D053773:Transforming Growth Factor beta1; C526316:CCN2 protein, rat; C115044:CCN5 protein, rat; C497804:Smad6 protein, rat; C498862:Acta2 protein, rat