Molecular regulation of CCN2 in the intervertebral disc: Lessons learned from other connective tissues

Abstract

Connective tissue growth factor (CCN2/CTGF) plays an important role in extracellular matrix synthesis, especially in skeletal tissues such as cartilage, bone, and the intervertebral disc. As a result there is a growing interest in examining the function and regulation of this important molecule in the disc. This review discusses the regulation of CCN2 by TGF-β and hypoxia, two critical determinants that characterize the disc microenvironment, and discusses known functions of CCN2 in the disc. The almost ubiquitous regulation of CCN2 by TGF-β, including that seen in the disc, emphasizes the importance of the TGF-β-CCN2 relationship, especially in terms of extracellular matrix synthesis. Likewise, the unique cross-talk between CCN2 and HIF-1 in the disc highlights the tissue and niche specific mode of regulation. Taken together the current literature supports an anabolic role for CCN2 in the disc and its involvement in the maintenance of tissue homeostasis during both health and disease. Further studies of CCN2 in this tissue may reveal valuable targets for the biological therapy of disc degeneration.

Advancing the cellular and molecular therapy for intervertebral disc disease

“…The most notable finding is the regulation of NP cell survival, matrix synthesis and apoptosis by hypoxia inducible factor (HIF) [47][48][49]. HIFs are transcription factors belonging to the PER-ARNT-SIM (PAS)…”

Key roles for the small leucine-rich proteoglycans in renal and pulmonary pathophysiology

“…The cysteine-rich cytokine, connective tissue growth factor (CTGF/CCN2) is a downstream mediator of TGF-β signaling [90] and plays an important role in the evolution of fibrotic disease [91, 92]. CTGF is expressed in response to TGF-β in a variety of cell types, including fibroblasts and renal proximal tubule epithelial cells [93], shows mitogenic and chemotactic properties, and induces the synthesis of collagen I, III, integrin β1 and fibronectin [94].…”

TGFβ regulates Galectin-3 expression through canonical Smad3 signaling pathway in nucleus pulposus cells: implications in intervertebral disc degeneration

“…TGFβ, a pleotropic cytokine expressed by NP cells is shown to control expression of many important extracellular matrix proteins such as aggrecan and collagen 2 and enzymes that contribute to glycosaminoglycan (GAG) synthesis like B3GAT3 [24, 25]. In addition, TGFβ controls expression of CCN2, an important matricellular protein concerned with matrix homeostasis and anti-inflammatory activities in the disc [21, 26–28]. Importantly, we and others have shown previously that the levels of TGFβ are elevated during disc degeneration [21, 29].…”