The advance of CCN3 in fibrosis

Abstract

The extracellular matrix (ECM) is comprised of various extracellular macromolecules, including collagen, enzymes, and glycoproteins, which offer structural and biochemical support to neighboring cells. After tissue injury, extracellular matrix proteins deposit in the damaged tissue to promote tissue healing. However, an imbalance between ECM production and degradation can result in excessive deposition, leading to fibrosis and subsequent organ dysfunction. Acting as a regulatory protein within the extracellular matrix, CCN3 plays a crucial role in numerous biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Many studies have demonstrated that CCN3 can reduce the production of ECM in tissues through diverse mechanisms thereby exerting an inhibitory effect on fibrosis. Consequently, CCN3 emerges as a promising therapeutic target for ameliorating fibrosis.

Blocking CCN2 Reduces Established Palmar Neuromuscular Fibrosis and Improves Function Following Repetitive Overuse Injury

“…We extended our studies, examining the effects of task and treatment on CCN3 on muscle, another member of the CCN family with anti-fibrotic properties [ 43 , 48 , 49 ]. We first verified the anti-CCN3 antibody with a Western blot loaded with recombinant CCN3 (rCCN3) protein ( Figure 4 A (left)).…”

“…It has been suggested that CCN family members and β-catenin interact with various MMPs [ 38 , 49 ]. Therefore, we checked for levels of MMP-1, -2, and -9.…”

“…These fibro-degenerative changes were ameliorated in the Rest/anti-CCN2 treated rats. This treatment also reduced protein expression levels of phosphorylated-β-catenin (a Wnt pathway protein shown to contribute to the pathogenesis of fibrotic disorders [ 55 ]) in muscles and the distal bone/entheses complex, increased expression of CCN3 (a CCN protein family member with tissue healing properties, including reductions in fibrosis [ 48 , 49 ]) in the same tissues, and reduced αSMA+ cells in flexor muscles, compared to HRHF-Untreated rats. In contrast, the Rest/IgG treatment reduced nerve fibrosis, but not muscle fibrosis (although it did reduce αSMA+ cells), and only partially reduced entheseal damage.…”

“…The CCN family members have roles in multiple tissue types throughout the body, interact with and modulate multiple proteins, and are considered as some as the principal coordinators of extracellular matrix remodeling [ 49 , 66 ]. CCN2 directly interacts with CCN3 and TGF-β, for example [ 66 , 67 ].…”

“…CCN2 is known to have autocrine feedback loops on itself and its binding partners [ 25 , 66 , 67 ], so that inhibition of its function results in a decrease in the expression of CCN2, but also in the many partners with whom it interacts. The changes in phosphorylated β-catenin and CCN3 observed in this study may be the result of downregulation of CCN2 after the anti-CCN2 (FG-3019) treatment [ 34 ] (discussed further below), or unknown physical interactions between CCN2 and 3 that mediate their antagonistic effects [ 49 , 68 , 69 ].The anti-CCN2 (FG-3019) could also act as a clearance antibody, removing CCN2 from the vicinity of the cells or interfering in its interactions with some of its putative binding partners [ 70 ].…”