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  • Review Article
  • Published:

Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets

Nature Reviews Drug Discovery volume 10, pages 945–963 (2011)Cite this article

Subjects

Key Points

  • CCNs are a family of extracellular matrix proteins that regulate diverse aspects of cellular functions, and are involved in inflammation and tissue repair.

  • Deregulation of CCN proteins is associated with many diseases; CCN proteins contribute to fibrosis, cancer and arthritis, as well as diabetic nephropathy and retinopathy.

  • Members of the CCN family of proteins may have opposing functions. For example, CCN2 and CCN4 are pro-fibrotic, whereas CCN1, CCN3 and CCN5 are antifibrotic.

  • Detection of CCN proteins or protein fragments in biological fluids may have diagnostic or prognostic value in some pathologies, including fibrosis and cancer.

  • In proof-of-principle studies, targeting CCN proteins has been shown to be therapeutically beneficial in fibrosis, cancer and diabetic nephropathy.

  • In clinical trials, targeting CCN2 has shown encouraging results in several human diseases, including fibrosis and diabetic nephropathy.

Abstract

Members of the CCN family of matricellular proteins are crucial for embryonic development and have important roles in inflammation, wound healing and injury repair in adulthood. Deregulation of CCN protein expression or activities contributes to the pathobiology of various diseases — many of which may arise when inflammation or tissue injury becomes chronic — including fibrosis, atherosclerosis, arthritis and cancer, as well as diabetic nephropathy and retinopathy. Emerging studies indicate that targeting CCN protein expression or signalling pathways holds promise in the development of diagnostics and therapeutics for such diseases. This Review summarizes the biology of CCN proteins, their roles in various pathologies and their potential as therapeutic targets.

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Figure 1: Transcriptional regulation of genes encoding CCN proteins*.
Figure 2: Molecular interactions through modular domains of CCN proteins.
Figure 3: Signalling mechanism of CCN1-induced senescence and crosstalk with TNF and FASL.
Figure 4: Role of CCN proteins in wound healing.

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Acknowledgements

We apologize to colleagues whose primary papers were not cited owing to space constraints. This work was supported in part by grants to L.F.L. from the US National Institutes of Health (AR61791, GM78492 and HL81390).

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  1. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, 900 S. Ashland Avenue, Chicago, 60607, Illinois, USA

    Joon-Il Jun & Lester F. Lau

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  1. Joon-Il Jun
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  2. Lester F. Lau
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Correspondence to Lester F. Lau.

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The authors declare no competing financial interests.

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FURTHER INFORMATION

Lester F. Lau's homepage

ClinicalTrials.gov website

Excaliard Pharmaceuticals — 10 January 2011 press release

Galena BioPharma — 7 September 2011 press release

The International CCN Society website

Glossary

Matricellular proteins

Dynamically expressed extracellular matrix proteins with a modular structure that have regulatory roles and are often involved in wound healing.

Matrix metalloproteinases

Members of a family of >20 zinc-dependent endopeptidases that are involved in the degradation of extracellular matrix proteins, cleavage of cell-surface receptors, release of apoptotic ligands, and activation of chemokines and cytokines.

Integrins

Members of a family of heterodimeric cell-surface signalling receptors that mediate cell–cell and cell–matrix interactions; they are composed of 18 α-subunits and 8 β-subunits, which constitute 24 known integrin heterodimers in mammals.

Immediate-early genes

Genes that are transcriptionally activated with rapid kinetics, without requiring de novo protein synthesis, by a range of stimuli including viral infection or various extracellular signals.

Low-density lipoprotein receptor-related protein

Members of this family of proteins are cell-surface receptors that bind a broad spectrum of ligands, facilitating endocytosis and the signalling of associated receptors.

Anoikis

Induction of programmed cell death by detachment of cells from the extracellular matrix.

Cellular senescence

A state of irreversible cell cycle arrest induced by various forms of cellular stresses including DNA damage, oncogene activation, oxidative stress, chromatin disruption and telomere erosion.

Senescence-associated secretory phenotype

A phenotype that is one of the characteristics of senescent cells and includes increased secretion of inflammatory cytokines and matrix-degrading enzymes, as well as downregulation of extracellular matrix proteins such as collagen.

Chondrocytes

Connective tissue cells that produce the cartilaginous matrix, including type II collagen and proteoglycans, and reside within the lacuna of the cartilage matrix.

Osteoblasts

Mononucleate cells that are responsible for bone formation. They produce osteoid, which is composed mainly of type I collagen, and are responsible for mineralization of the osteoid matrix.

Atrioventricular septal defects

A form of congenital heart defect in which the heart chambers are poorly formed as a result of impairments in the endocardial cushions, which contribute to the formation of the atrial and ventricular septa, as well as the mitral and tricuspid valves.

Platelet α-granules

Cytoplasmic granules containing many protein factors that are involved in inflammation and wound repair. They are synthesized predominantly in megakaryocytes and include cell-adhesive proteins, growth and coagulation factors, and protease inhibitors, which are released following platelet activation at sites of vessel injury.

Epithelial-to-mesenchymal transition

A process — typically involving repression of E-cadherin expression — in which epithelial cells lose their adhesive properties and gain mobility. This transition is essential for many developmental processes and occurs during oncogenic transformation.

Microalbuminuria

A condition in which small amounts of albumin leak into the urine following injury or damage to the kidney, which is indicative of abnormal permeability in the renal glomerulus.

Balloon angioplasty

A method of mechanically widening a blood vessel that has typically been obstructed as a result of atherosclerosis. The method involves passing a collapsed balloon catheter through the obstructed area and inflating the balloon to open up the blood vessel as the catheter is withdrawn.

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Jun, JI., Lau, L. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 10, 945–963 (2011). https://doi.org/10.1038/nrd3599

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