Yin and Yang revisited: CCN3 as an anti-fibrotic therapeutic?

Abstract

Fibrotic diseases are a significant cause of mortality. It is being increasingly appreciated that the cellular microenvironment plays a key role in promoting pathological fibrosis. A previous Bits and Bytes described an elegant series of experiments published by Bruce Riser and colleagues (Am J Pathol. 2009: 174:1725) that showed that CCN3 (nov) antagonizes the fibrogenic effects of CCN2.and hence could represent a novel anti-fibrotic therapy. They have continued their excellent work and have recently used the ob/ob mouse as a model of obesity and diabetic nephropathy to show that CCN3 could block the induction of profibrotic gene expression, fibrosis and loss of kidney function (Am J Pathol. 2014;184:2908-21). Also, reversal of fibrosis was observed. Thus this paper provides strong evidence that CCN3 may be used as a novel therapy to treat diabetes caused by obesity.

Blocking CTGF/CCN2 reduces established skeletal muscle fibrosis in a rat model of overuse injury

“…In mechanically strained fibroblasts, CCN3 levels are low during mechanical stress and increase again after relaxation 23 . Interestingly, CCN3 has antifibrogenic roles and antagonizes the fibrogenic effects of CCN2 21,22 . Perhaps its inverse expression pattern from CCN2 and increase with the FG‐3019 treatment is one mechanism through which the FG‐3019 agent is reducing muscle fibrosis.…”

“…CCN2 is a secreted matricellular protein with four modular domains that independently interact with different molecules, such as collagen and proteoglycans in the extracellular matrix 20 . CCN1/Cyr61 (also known as Cysteine‐rich angiogenic inducer 61) and CCN3/NOV (also known as nephroblastoma overexpressed) are two family members that can have similar or opposing functions in fibrogenic processes as CCN2, respectively 21‐23 . Downregulation of CCN2 by antisense or siRNA treatment reduces liver fibrosis and limits hypertrophic scarring without affecting wound healing 24,25 .…”

Blocking CCN2 Reduces Progression of Sensorimotor Declines and Fibrosis in a Rat Model of Chronic Repetitive Overuse

“…CCN3 is anti‐fibrogenic, antagonizes the fibrogenic effects of CCN2, and has an inverse expression pattern than CCN2 . Its downregulation in task animals when CCN2 levels are increasing warrants further examination in fibrogenic musculoskeletal disorders since provision of CCN3 or derived peptides has been postulated as a viable anti‐fibrotic treatment for diabetic nephropathy …”

“…Cellular communication network factor 2 (CCN2; CTGF) is a secreted matricellular protein with four modular domains that independently interact with different molecules, such as collagen and proteoglycans in the extracellular matrix . CCN1 (Cyr6) and CCN3 (NOV) are two family members that can have similar or opposing functions in fibrogenic processes as CCN2, respectively . Since fibrosis is thought to distort dynamic properties of tissue due to adherence of adjacent structures, it may also contribute to functional and biomechanical tissue declines .…”

Erratum to: Pick of the Year 2014

“…Fisher (2015) Stem cell quest by Alexandra Irvine (2015) Lovastatin rescues human and mice cartilage disorders by Satoshi Kubota (2015) Yin and Yang revisited: CCN3 as an anti-fibrotic therapeutic? By Andrew Leask (2015) Another dimension to the importance of the extracellular matrix in fibrosis by Laure Rittié (2015) Therapeutic targeting of the thrombospondin-1 receptor CD47 to treat liver cancer by David D. Roberts, Sukhbir Kaur and David R. Soto-Pantoja (2015) …”