CTGF

CTGF, also known as CCN2 or connective tissue growth factor, is a is_associated_with::matricellular protein of the CCN family of is_associated_with::extracellular matrix-associated is_associated_with::heparin-binding proteins (see also is_associated_with::CCN intercellular signaling protein). CTGF has important roles in many biological processes, including is_associated_with::cell adhesion, migration, proliferation, is_associated_with::angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.

Structure and binding partners
Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved, is_associated_with::cysteine-rich domains. These domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, the von Willebrand type C repeats (vWC) domain, the thrombospondin type 1 repeat (TSR) domain, and a C-terminal domain (CT) with a is_associated_with::cysteine knot motif. CTGF exerts its functions by binding to various cell surface receptors in a context-dependent manner, including is_associated_with::integrin receptors,  cell surface  heparan sulfate proteoglycans (HSPGs), LRPs, and TrkA. In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with is_associated_with::aggrecan, the TSR domain interacts with is_associated_with::VEGF, and the CT domain interacts with members of the TGF-β superfamily, is_associated_with::fibronectin, is_associated_with::perlecan, is_associated_with::fibulin-1, slit, and is_associated_with::mucins.

Role in development
Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severe is_associated_with::chondrodysplasia. Ctgf-null mice also show defects in angiogenesis, with impaired interaction between endothelial cells and pericytes and collagen IV deficiency in the endothelial basement membrane. CTGF is also important for is_associated_with::pancreatic beta cell development, and is critical for normal is_associated_with::ovarian follicle development and is_associated_with::ovulation.

Clinical significance
CTGF is associated with is_associated_with::wound healing and virtually all is_associated_with::fibrotic pathology. It is thought that CTGF can cooperate with is_associated_with::TGF-β to induce sustained is_associated_with::fibrosis and to exacerbate extracellular matrix production in association other fibrosis-inducing conditions. Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung, and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reduces bleomycin-induced skin fibrosis.

In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies, is_associated_with::diabetic nephropathy and is_associated_with::retinopathy, arthritis, and cardiovascular diseases. Several clinical trials are now ongoing that investigate the therapeutic value of targeting CTGF in fibrosis, diabetic nephropathy, and is_associated_with::pancreatic cancer.