# WNT1-inducible-signaling pathway protein 1

WNT1-inducible-signaling pathway protein 1 (WISP-1), is a member of the CCN protein family and should correctly be referred to as CCN4 as suggested by the International CCN Society. It is a matricellular protein that in humans is encoded by the WISP1 gene.

## Structure

CCN4/WISP-1 is highly homologous to CYR61 (CCN1) and CTGF (CCN2), and is a member of the CCN family of secreted, extracellular matrix (ECM)-associated signaling proteins (CCN intercellular signaling protein). The CCN family of proteins shares a common molecular protein structure, characterized by an N-terminal secretory signal peptide followed by four distinct domains with homologies to insulin-like growth factor binding protein (IGFBP), von Willebrand type C repeats (vWC), thrombospondin type 1 repeat (TSR), and a cysteine knot motif within the C-terminal (CT) domain. This family of proteins regulates diverse cellular functions, including cell adhesion, migration, proliferation, differentiation, and survival.

## Role in bone development

CCN4/WISP-1 promotes mesenchymal cell proliferation and osteoblastic differentiation, and represses chondrocytic differentiation. WISP-1 binds BMP2 and enhances BMP2 function in osteogenesis. These activities may be modulated by its direct binding to decorin and biglycan, two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue.

## Clinical significance

In cells CCN4 has a range of actions including stimulating cell migration and cell proliferation and is a pro-survival factor. These effects appear to be conserved across a range of cell types including vascular smooth muscle cells, monocytes, fibroblasts and cancer cell lines. The effects are also preserved across species from mouse and rat to human cells studied in vitro.

### Cancer

Expression of CCN4 promotes tumor growth, and high CCN4 expression correlates with advanced tumors of the brain, breast, colon, and lung. CCN4 appears to inhibit metastasis although expression of a CCN4 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of gastric carcinoma cells.

### Pulmonary fibrosis

Recombinant CCN4 enhances ECM deposition in human fibroblasts, suggesting that it might play a role in matrix remodeling in vivo. WISP-1 is upregulated in human patients with idiopathic pulmonary fibrosis and in a mouse model of bleomycin-induced lung fibrosis.
Orotracheal application of CCN4 neutralizing antibodies to the lung ameliorates bleomycin-induced lung fibrosis, raising the possibility that CCN4 might be a potential target for anti-fibrotic therapy.

### Cardiac fibrosis

CCN4 activates human cardiac fibroblasts via integrin β1-Akt signaling pathway to induce collagen deposition and promote fibrosis. In a mouse model of cardiac fibrosis deletion of the CCN4 gene reduced the severity of fibrosis.

### Myocardial injury

CCN4 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase, and inhibits TNF-induced cell death in cardiomyocytes.

### Intimal thickening

In a mouse carotid artery ligation model of intimal thickening, deletion of the CCN4 gene reduced intimal thickening, while elevation of CCN4 using an adenovirus increased intimal thickening. Knocking out the CCN4 gene reduced the number of proliferating cells. Mouse aortic vascular smooth muscle cells in tissue culture addition of CCN4 increased cell migration and this effect was integrin dependent.

### Atherosclerosis

In samples from atherosclerotic human coronary arteries unstable plaques had lower CCN4 compared to stable plaques. Loss of CCN4 resulted in more apoptosis, leading to loss of the plaque fibrous cap, increased lipid core size and more unstable plaque phenotype. Rupture of these unstable plaques can lead to plaque growth via incorporation of thrombus into a new layer of plaque. Using the high fat fed ApoE mouse model of atherosclerosis (created by) Jan Breslow), elevation of CCN4 using helper dependent adenovirus reduced apoptosis, number of macrophages and lipid core size and reduced atherosclerosis. Knocking out the CCN4 gene increased apoptosis and the severity of atherosclerosis.

### Aortic aneurysm

In a mouse model of aortic aneurysm CCN4 increased the severity of aneurysms and increased cell proliferation in the wall of the aorta. Human blood monocytes in vitro migrated more following the addition of CCN4; and adhesion of the monocytes to a layer of human umbilical vein endothelial cells was also increased.