CCN2 and CCN5 exerts opposing effect on fibroblast proliferation and transdifferentiation induced by TGF‐β

Abstract

Epidural fibrosis might occur after lumbar discectomy and contributes to failed back syndrome. Transforming growth factor (TGF)-β has been reported to influence multiple organ fibrosis, in which connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed 2 (CCN2) and CCN5 are involved. However, the effect of CCN2 and CCN5 on TGF-β induced fibrosis has not yet been elucidated. This study reports that CCN2 and CCN5 play opposing roles in cell proliferation and transdifferentiation of human skin fibroblasts or rabbit epidural scar-derived fibroblasts exposed to TGF-β. We observed that TGF-β1 induced fibroblasts proliferation and differentiation in a dose-dependent manner (from 0 μg/L to 20 μg/L). Meanwhile, CCN2 expression is up-regulated while CCN5 expression is inhibited by TGF-β1 exposure. Furthermore, it is demonstrated that CCN2 overexpression leads to promoted proliferation and elevated collagen and α-smooth muscle actin (α-SMA) expression, which are inhibited by CCN5 overexpression. Moreover, it is shown that the cysteine knot (CT) domain, present in CCN2 but absent in CCN5, plays an essential part in fibroblast proliferation and differentiation. Additionally, enhanced TGF-β and CCN2 expression but decreased CCN5 expression is found in rabbit epidural scar-derived fibroblasts. Overall, the results show the opposing effects of CCN2 and CCN5 on fibroblast proliferation and transdifferentiation induced by TGF-β.

Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis

“…PDGFAA upregulated proliferation only in SSc fibroblasts (Figure 2a) and crenolanib blocked this response. We also examined the mitogenic effect of CCN2, which has previously been reported to indirectly induce fibroblast proliferation (Xu et al, 2015). Interestingly, while CCN2 alone had no effect, addition of PDGFAA together with CCN2 induced proliferation of HC fibroblasts with similar potency to that of PDGFBB (Figure 2b).…”

CCN5 Reduces Ligamentum Flavum Hypertrophy by Modulating the TGF‐β Pathway

“…As explained in the introduction, CCNs (sometimes called matricellular proteins) are involved in cell‐to‐cell signaling and play important roles in ECM regulation . CCN5 is unique because it lacks a C‐terminal repeat domain and acts as a negative regulator of other CCNs, especially CCN2 . Several recent studies have established the anti‐fibrotic and anti‐hypertrophic effects of CCN5, and the majority of them have shown that CCN5 may modulate the TGF‐β pathway when acting on fibroblasts …”

Lanatoside C protects mice against bleomycin‐induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation

“…Fibroblast differentiation is an additional critical aetiology in the development of pulmonary fibrosis. Accompanying changes in the microenvironment include the overproduction of a key factor, TGF‐β1, resulting in the activation of fibroblasts into myofibroblasts and production of abundant levels of ECM in the interstitial tissues of the lungs, leading to irreversible damage to lung architecture and pulmonary fibrosis . Our results revealed that lanatoside C treatment was capable of reducing the expression of α‐SMA, fibronectin and collagens I and III in response to TGF‐β1, indicating a suppression role for lanatoside C during the differentiation process of fibroblasts into myofibroblasts.…”