CTGF

Official Full Name

cellular communication network factor 2

Organism

Homo sapiens

GeneID

1490

Background

The protein encoded by this gene is a mitogen that is secreted by vascular endothelial cells. The encoded protein plays a role in chondrocyte proliferation and differentiation, cell adhesion in many cell types, and is related to platelet-derived growth factor. Certain polymorphisms in this gene have been linked with a higher incidence of systemic sclerosis. [provided by RefSeq, Nov 2009]

Synonyms

CTGF; NOV2; HCS24; IBP-8; IGFBP8;

Bio Chemical Class

mRNA target

Protein Sequence

MTAASMGPVRVAFVVLLALCSRPAVGQNCSGPCRCPDEPAPRCPAGVSLVLDGCGCCRVCAKQLGELCTERDPCDPHKGLFCHFGSPANRKIGVCTAKDGAPCIFGGTVYRSGESFQSSCKYQCTCLDGAVGCMPLCSMDVRLPSPDCPFPRRVKLPGKCCEEWVCDEPKDQTVVGPALAAYRLEDTFGPDPTMIRANCLVQTTEWSACSKTCGMGISTRVTNDNASCRLEKQSRLCMVRPCEADLEENIKKGKKCIRTPKISKPIKFELSGCTSMKTYRAKFCGVCTDGRCCTPHRTTTLPVEFKCPDGEVMKKNMMFIKTCACHYNCPGDNDIFESLYYRKMYGDMA

Open

Disease

Fibrosis, Keloid/hypertrophic scar

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

The CCN2 gene (Cellular Communication Network Factor 2), also known as CTGF (Connective Tissue Growth Factor), encodes a protein primarily secreted by vascular endothelial cells, playing crucial biological roles. CCN2 functions in various cell types, notably in chondrocyte proliferation and differentiation, cell adhesion, and its association with platelet-derived growth factors. The polymorphism of the CCN2 gene is closely related to the occurrence of certain diseases, including systemic sclerosis. Beyond its cellular biology roles, CCN2 acts as a key regulator responding to mechanical stress, contributing significantly in different cell types and tissues.

Role of CCN2 in Chondrocytes

Cartilage is a specialized tissue lacking both blood vessels and lymphatic tissue, relying on synovial fluid movement generated by joint motion for nutrition, making chondrocytes its sole cellular component. The metabolic activity of chondrocytes is influenced by various mechanical stress factors, with CCN2 being a key player. Its expression significantly increases under mechanical load, promoting chondrocyte proliferation and differentiation. Research indicates a close relationship between CCN2 expression and mechanical load on chondrocytes. Under cyclic mechanical loading, CCN2 expression varies, where periodic load helps maintain chondrocyte activity, while continuous loading may induce unfavorable changes.

CCN2 as a Regulator Responding to Mechanical Stress

CCN2 not only interacts closely with intracellular signaling pathways regulating cellular functions but also plays a crucial role in responding to mechanical load. Mechanical stress activates diverse signaling pathways through mechanisms like mechanosensitive ion channels, integrins, Rho GTPase family, and GPCRs, leading to cellular morphology changes and gene expression regulation. Notably, RhoA GTPase is vital in cellular mechanotransduction, where its activation induces CCN2 expression, elucidating its mechanism in fibroblasts and vascular smooth muscle cells.

Figure 1 illustrates the potential mechanoreceptors in chondrocytes that regulate CCN2 expression, activated by membrane stretch, fluid shear stress, or LIPUS treatment. Figure 1. Schematic diagram of possible mechanoreceptors regulating CCN2 expression. (Nishida T, et al., 2020)

Interaction of CCN2 with YAP/TAZ in Mechanical Stress

Mechanical stress affects gene expression by modulating cytoskeletal dynamics, involving significant transcription coactivators, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), regulated by the Hippo signaling pathway. Under mechanical stress, YAP and TAZ promote CCN2 expression through interactions with F-actin stress fibers. In various cell types, YAP and TAZ regulate CCN2 gene expression by shuttling between the cytoplasm and nucleus. Studies reveal that mechanical stretching moves YAP/TAZ to the nucleus, activating genes related to cell proliferation and differentiation, including CCN2.

Relationship of CCN2 with Integrins and TRPV4 Channels

Integrins are proteins on the surface of cells that can feel outside pressure. They link to the cell's internal structure and signaling molecules, which helps start various communication processes inside the cell. CCN2 helps cells connect with the surrounding matrix, acting as a key link for integrins. Research indicates that CCN2 connects with integrins to trigger signaling pathways, which affects the growth and development of cartilage cells (chondrocytes). TRPV4 is an important ion channel in chondrocytes that responds to mechanical stress. When there is a mechanical load, TRPV4 allows calcium to enter the cells. This process helps control genes such as SOX9 and type II collagen, which support the development of chondrocytes.

Role of CCN2 in Systemic Sclerosis

Systemic sclerosis is a common autoimmune disease that causes thickening of the skin and harm to internal organs. Recent studies link variations in the CCN2 gene to the development of systemic sclerosis. High levels of CCN2 in the smooth muscle cells of blood vessels are important for the development of the disease. CCN2 may play a big role in causing fibrosis in systemic sclerosis by encouraging the growth and development of fibroblasts. Additionally, its association with platelet-derived growth factors could worsen the disease.

Potential Role of CCN2 in Other Diseases

CCN2 plays an important part in cartilage and systemic sclerosis, and it may also influence other illnesses. In kidney fibrosis, CCN2 is an important factor that can worsen the condition by encouraging the growth and change of certain kidney cells. CCN2 is important for normal body functions and also plays a key part in diseases.

Therapeutic Prospects of CCN2

Given its critical roles across cell types, CCN2 emerges as a potential target in disease treatment. In conditions like systemic sclerosis and kidney fibrosis, inhibiting CCN2 expression or function could be an effective therapeutic strategy. Research suggests that modulating mechanical stress and CCN2 expression may lead to breakthroughs in treating cartilage injuries and fracture healing.

References:

Nishida T, Kubota S. Roles of CCN2 as a mechano-sensing regulator of chondrocyte differentiation. Jpn Dent Sci Rev. 2020 Nov;56(1):119-126.
Fadl A, Leask A. CCN2: a potential contributor to gingival overgrowth. J Oral Biosci. 2024 Nov 7:100587.

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