Expression of CTGF/CCN2 in response to LPA is stimulated by fibrotic extracellular matrix via the integrin/FAK axis

Abstract

Fibrosis is a common feature of several chronic diseases and is characterized by exacerbated accumulation of ECM. An understanding of the cellular and molecular mechanisms involved in the development of this condition is crucial for designing efficient treatments for those pathologies. Connective tissue growth factor (CTGF/CCN2) is a pleiotropic protein with strong profibrotic activity. In this report, we present experimental evidence showing that ECM stimulates the synthesis of CTGF in response to lysophosphatidic acid (LPA).The integrin/focal adhesion kinase (FAK) signaling pathway mediates this effect, since CTGF expression is abolished by the use of the Arg-Gly-Asp-Ser peptide and also by an inhibitor of FAK autophosphorylation at tyrosine 397. Cilengitide, a specific inhibitor of αv integrins, inhibits the expression of CTGF mediated by LPA or transforming growth factor β1. We show that ECM obtained from decellularized myofibroblast cultures or derived from activated fibroblasts from muscles of the Duchenne muscular dystrophy mouse model ( mdx) induces the expression of CTGF. This effect is dependent on FAK phosphorylation in response to its activation by integrin. We also found that the fibrotic ECM inhibits skeletal muscle differentiation. This novel regulatory mechanism of CTGF expression could be acting as a positive profibrotic feedback between the ECM and CTGF, revealing a novel concept in the control of fibrosis under chronic damage.

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα+fibroblasts

“…7C,E, Fig. S7C), as previously reported (Riquelme-Guzmán et al, 2018; Vial et al, 2008). Finally, we did not find changes in TCF7L2 subcellular distribution in myoblasts after TGF-β treatment (Fig.…”

Connective tissue growth factor promotes chemotaxis of preosteoblasts through integrin α5 and Ras during tensile force-induced intramembranous osteogenesis

“…Our immunohistochemical data showed CTGF distribution inside integrin α5 + cells at the osteogenic front. Integrin signaling induces CTGF expression in myoblastic C2C12 cells 42 . CTGF upregulates integrin α5 expression in chondrocytes 25 .…”

Role of Matricellular CCN Proteins in Skeletal Muscle: Focus on CCN2/CTGF and Its Regulation by Vasoactive Peptides

“…The characteristic hypoxia of damaged tissue, with stabilization of hypoxia-inducible factor 1α (HIF-1α), is involved in establishing fibrosis in skeletal muscle by synergistically upregulate CCN2/CTGF in myotubes and myofibers when TGF-β is present, as in damaged skeletal muscle [ 22 , 67 , 68 ]. Also, the bioactive lipid lysophosphatidic acid (LPA), involved in inflammation and fibrosis in different tissues, including skeletal muscle [ 119 ], can induce CCN2/CTGF expression [ 50 , 52 , 120 ]. Some of the mechanisms that control the expression of CCN2/CTGF in response to LPA crosstalks with other signaling pathways such as TGF-β and JNK [ 50 , 52 , 120 ] and the hippo-YAP pathway [ 121 ].…”

“…Also, the bioactive lipid lysophosphatidic acid (LPA), involved in inflammation and fibrosis in different tissues, including skeletal muscle [ 119 ], can induce CCN2/CTGF expression [ 50 , 52 , 120 ]. Some of the mechanisms that control the expression of CCN2/CTGF in response to LPA crosstalks with other signaling pathways such as TGF-β and JNK [ 50 , 52 , 120 ] and the hippo-YAP pathway [ 121 ]. The Yes-associated protein (YAP), the core effector of the Hippo pathway, and the TEAD transcription factors are critical regulators of muscle mass and mechanotransduction in skeletal muscle [ 122 , 123 ].…”