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

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. Here, the authors discuss how aberrant expression and activity of the CCN matricellular proteins contribute to the pathobiology of diseases linked to inflammation or chronic tissue injury, and they highlight how these proteins could be potential therapeutic targets. 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.