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CTGF

Connective tissue growth factor (CTGF), also known as CCN2, is a cysteine-rich, secreted matricellular protein belonging to the CCN family of regulatory proteins.^[1] It consists of 349 amino acids forming a 38 kDa polypeptide with four modular domains: an insulin-like growth factor-binding protein (IGFBP) domain, a von Willebrand factor type C (VWC) domain, a thrombospondin type 1 (TSP1) repeat, and a C-terminal cysteine knot (CT) domain, which enable interactions with growth factors, integrins, extracellular matrix components, and receptors.^[1] Originally discovered in 1991 as a mitogen secreted by human vascular endothelial cells, CTGF modulates key cellular processes including adhesion, migration, proliferation, differentiation, and extracellular matrix (ECM) production.^[2] In normal physiology, it plays critical roles in wound healing, angiogenesis, chondrogenesis, osteogenesis, and embryonic development, with CTGF-null mice exhibiting severe skeletal defects and perinatal lethality.^[3]^[1] Dysregulated CTGF expression is prominently associated with pathological conditions, particularly fibrosis in organs such as the liver, lungs, kidneys, heart, and pancreas, where it acts as a downstream mediator of transforming growth factor-beta (TGF-β) to drive myofibroblast activation, epithelial-to-mesenchymal transition, and excessive ECM deposition, thereby perpetuating tissue remodeling and scarring.^[3] In cancer, CTGF contributes to tumor progression in over 30 types, including breast, pancreatic, and osteosarcoma, by promoting angiogenesis, invasion, and metastasis through interactions with integrins and VEGF, although it may suppress growth in certain contexts like lung or colorectal cancers depending on the stage and microenvironment.^[1] Elevated CTGF levels are also observed in chronic diseases such as diabetes, systemic sclerosis, and chronic obstructive pulmonary disease (COPD), correlating with disease severity.^[3] Therapeutic targeting of CTGF has emerged as a promising strategy, with anti-CTGF monoclonal antibodies like FG-3019 (pamrevlumab) demonstrating efficacy in preclinical models of fibrosis by reversing ECM accumulation and vascular stiffening, and investigated in phase III clinical trials for idiopathic pulmonary fibrosis (IPF), though these trials did not meet their primary endpoints and were discontinued in 2023.^[3]^[4] Similarly, siRNA and antisense oligonucleotides against CTGF have prevented or attenuated fibrosis in animal studies of liver injury and diabetic nephropathy, highlighting its potential as a biomarker and intervention target.^[1]

Gene and Expression

Gene Structure and Location

The CTGF gene, officially known as CCN2 (cellular communication network factor 2), is located on the long arm of human chromosome 6 at cytogenetic band 6q23.2, with genomic coordinates spanning 131,948,176 to 131,951,372 (GRCh38 assembly).^[5]^[6] The orthologous gene in mice (Ctgf) maps to chromosome 10.^[7] This compact gene covers approximately 3.2 kb of genomic DNA and comprises 5 exons separated by 4 introns, with the exons encoding distinct functional modules of the protein.^[5]^[8] The primary transcript is a mature mRNA of about 2.3 kb in length (ENST00000367976.4), which is processed from the genomic sequence and translates into a 349-amino acid precursor protein, including a signal peptide for secretion.^[5]^[8]^[9] As a member of the CCN gene family—alongside CYR61 (CCN1) and NOV (CCN3)—the CTGF gene shows strong evolutionary conservation across mammalian species, reflecting its fundamental role in cellular signaling processes.^[9]^[5]

Regulation of Expression

The expression of connective tissue growth factor (CTGF), also known as CCN2, is primarily induced by transforming growth factor-β (TGF-β) signaling through the canonical Smad pathway. Upon TGF-β ligand binding to its receptors, Smad2 and Smad3 are phosphorylated and form a complex with Smad4, which translocates to the nucleus and binds to specific Smad-binding elements in the CTGF promoter, thereby activating transcription.^[10] This mechanism is conserved across various cell types and is a key driver of CTGF upregulation in response to TGF-β stimulation.^[11] In addition to TGF-β, CTGF expression is regulated by environmental cues such as hypoxia via hypoxia-inducible factor-1 (HIF-1). Under low oxygen conditions, HIF-1α stabilizes and dimerizes with HIF-1β to bind hypoxia response elements upstream of the CTGF gene, directly promoting its transcription in cells like dermal fibroblasts.^[12] Similarly, mechanical stress influences CTGF levels through integrin-mediated signaling; tensile forces activate integrins, triggering intracellular pathways like focal adhesion kinase that enhance CTGF promoter activity, particularly in fibroblasts exposed to stretch or shear.^[13]^[14] Post-transcriptional regulation of CTGF involves microRNAs (miRNAs) and epigenetic modifications. For instance, miR-18b targets the 3'-untranslated region of CTGF mRNA, suppressing its translation and reducing protein levels, as observed in contexts like cancer and fibrosis where miR-18b is dysregulated.^[15] Epigenetically, histone acetylation at the CTGF promoter, facilitated by coactivators like p300/CBP in response to TGF-β, loosens chromatin structure to facilitate transcription, while inhibitors like trichostatin A can further enhance this acetylation and CTGF expression in renal cells.^[16]^[17] CTGF exhibits tissue-specific expression patterns, with notably high levels in fibroblasts, where it is robustly induced during extracellular matrix remodeling, and in endothelial cells under stress conditions like ischemia.^[18]^[19] During wound healing, CTGF mRNA and protein are transiently upregulated in the early phases, primarily in fibroblasts and granulation tissue, to support tissue repair without persistent fibrosis.^[20]

Protein Structure and Function

Domain Architecture

The connective tissue growth factor (CTGF), also known as CCN2, is synthesized as a 349-amino acid precursor protein with a calculated molecular mass of 38,091 Da, which includes an N-terminal signal peptide spanning residues 1–24.^[21] Following cleavage of the signal peptide, the mature protein consists of residues 25–349 and exhibits an apparent molecular weight of approximately 38 kDa, influenced by post-translational modifications.^[22] This modular structure enables CTGF's multifunctionality as a matricellular protein. CTGF's domain architecture comprises four distinct, conserved modules that contribute to its biological versatility. The N-terminal insulin-like growth factor-binding protein (IGFBP) domain (residues 25–140) facilitates modulation of growth factors such as IGF-1.^[1] Adjacent to it is the von Willebrand factor C (VWC) domain (residues 141–224), which mediates interactions with growth factors and extracellular matrix components.^[23] The central thrombospondin type 1 (TSP1) domain (residues 225–279) promotes cell adhesion via recognition motifs for integrins and other receptors.^[24] The C-terminal (CT) domain (residues 280–349), featuring a cysteine knot motif, mediates binding to heparin and integrins, enhancing CTGF's association with the extracellular environment.^[25] These domains are connected by flexible hinge regions susceptible to proteolytic cleavage, allowing independent or combinatorial functions. Post-translational modifications further refine CTGF's structure and stability. N-linked glycosylation occurs at specific asparagine residues, notably Asn28 in the IGFBP domain and Asn225 in the TSP1 domain, which influence protein folding, secretion, and activity.^[24] Additionally, CTGF contains 38 cysteine residues that form 17 intramolecular disulfide bonds, critical for maintaining the tertiary structure of each domain, particularly the compact cysteine-rich CT domain with its characteristic knot.^[14] These bonds, distributed across the protein, prevent unfolding and support its secretion. CTGF demonstrates potential for oligomerization, often existing as dimers or higher-order complexes stabilized by interdomain interactions, which may enhance its signaling capacity in the extracellular space.^[26] As a secreted matricellular protein, CTGF is released from cells into the extracellular matrix, where it modulates tissue architecture without being a structural component itself.^[27]

Binding Partners and Interactions

Connective tissue growth factor (CTGF), also known as CCN2, binds to integrins such as αvβ3 and α5β1 primarily through its thrombospondin type 1 (TSP1) and C-terminal (CT) domains, facilitating cell adhesion and downstream signaling events.^[28] These interactions enable CTGF to promote integrin-mediated processes like focal adhesion formation and cell migration, with the CT domain containing a conserved GVCTDGR motif critical for αvβ3 engagement.^[29] The domain-specific contributions to these bindings underpin CTGF's role in modulating cellular responses to the extracellular environment.^[30] CTGF interacts with several growth factors to amplify or modulate their activities, particularly enhancing profibrotic signaling. It binds transforming growth factor-β (TGF-β) via its von Willebrand factor C (vWC) and TSP1 domains, stabilizing TGF-β receptor interactions and potentiating TGF-β-induced effects on extracellular matrix production.^[30] With vascular endothelial growth factor (VEGF), CTGF forms complexes through TSP1 and CT domains that inhibit VEGF receptor binding and angiogenesis, as demonstrated by a dissociation constant of approximately 1.8 nmol/L for VEGF-A. CTGF also exhibits weak binding to platelet-derived growth factor-B (PDGF-B) via its cystine-knot domain, with a dissociation constant of 43 nmol/L, which promotes PDGF receptor β phosphorylation and enhances proliferative signaling in fibroblasts.^[31] CTGF associates with key extracellular matrix (ECM) components to influence matrix assembly and stability, often through heparin-binding motifs. It binds fibronectin via its insulin-like growth factor-binding protein (IGFBP) and CT domains, supporting cell adhesion to ECM scaffolds. Interactions with perlecan occur via heparin-binding sites in the TSP1 domain, regulating chondrocyte proliferation and differentiation. CTGF also engages collagen indirectly through cystine-knot domain associations, contributing to ECM organization.^[30] These molecular partnerships enable CTGF to modulate intracellular signaling pathways critical for cellular remodeling. Binding to integrins and growth factors activates the MAPK/ERK pathway via vWC, TSP1, and CT domains, driving gene expression changes.^[30] CTGF further stimulates PI3K/Akt signaling through integrin engagement, promoting survival and migration.^[32] Additionally, CTGF influences RhoA activation, leading to cytoskeletal reorganization and actin stress fiber formation.^[33]

Physiological Roles

Role in Development

Connective tissue growth factor (CTGF), also known as CCN2, plays a critical role in embryonic development by modulating cellular processes such as proliferation, differentiation, migration, and extracellular matrix remodeling essential for tissue formation. During embryogenesis, CTGF expression is dynamically regulated, with high levels observed in mesenchymal tissues undergoing patterning and morphogenesis. In skeletogenesis, CTGF is indispensable for chondrocyte proliferation, hypertrophy, and endochondral ossification. It coordinates chondrogenesis by promoting the proliferation of growth plate chondrocytes and their subsequent hypertrophic differentiation, while also facilitating angiogenesis within the hypertrophic zone to support bone formation. Studies in mouse models demonstrate that CTGF deficiency leads to impaired chondrocyte proliferation at embryonic day 14.5 (E14.5), expanded hypertrophic zones, and defective mineralization, resulting in skeletal dysmorphisms such as reduced trabecular bone collagen and delayed ossification in long bones and craniofacial structures.^[34] CTGF contributes to cardiovascular development through persistent expression in vascular endothelium and the heart, particularly in high-pressure regions, supporting vessel formation and cardiac tissue remodeling. Although direct roles in cardiac cushion formation and valve morphogenesis remain linked to its downstream effects in TGF-β signaling pathways, CTGF's presence in developing myocardium and endocardium underscores its involvement in these processes. CTGF facilitates implantation and placentation by promoting uterine epithelial and decidual cell adhesion, migration, and extracellular matrix production during the peri-implantation period. In mice, CTGF is highly expressed in luminal and glandular epithelium on days 1.5–3.5 of pregnancy, decreases around day 4.5 coinciding with blastocyst attachment, and then surges in decidual cells by days 5.5–6.5, aiding trophoblast invasion and placental bed establishment. Additionally, CTGF supports neural crest cell migration and mesenchymal condensation, particularly for craniofacial skeleton formation derived from neural crest progenitors, where its absence disrupts patterning and ossification.^[35] Knockout studies in mice reveal CTGF's essential functions, with homozygous null embryos exhibiting neonatal lethality due to respiratory failure from pulmonary hypoplasia and rib deformities. Skeletal defects include impaired bone formation in limbs and skull, while skin development proceeds normally, indicating non-essentiality in dermatogenesis. Partial redundancy is evident with other CCN family members, such as CCN3 (NOV), whose expression increases in CTGF-null chondrocytes to mitigate some chondrogenic impairments.^[36]

Role in Tissue Homeostasis and Repair

Connective tissue growth factor (CTGF), also known as CCN2, plays a critical role in maintaining tissue integrity during adult wound healing by orchestrating fibroblast recruitment, vascularization, and extracellular matrix (ECM) remodeling. In response to injury, CTGF stimulates the chemotaxis and proliferation of fibroblasts through its IGFBP and VWC domains, facilitating their migration to the wound site and subsequent differentiation into myofibroblasts that deposit collagen and other ECM components essential for tissue restoration.^[37] Additionally, CTGF enhances angiogenesis by upregulating vascular endothelial growth factor (VEGF) expression via activation of PI3K/AKT, ERK, and NF-κB pathways, which promotes endothelial cell migration and tube formation to ensure nutrient supply during repair.^[38] This coordinated action supports timely granulation tissue formation and re-epithelialization without excessive scarring in normal healing processes.^[39] In skeletal tissues, CTGF contributes to homeostasis and adaptive repair by regulating bone remodeling and cartilage maintenance, particularly under mechanical loading. Mechanical stress induces CTGF expression in osteocytes and chondrocytes, where it promotes chondrocyte proliferation and differentiation through MAPK/ERK and PI3K/AKT signaling, thereby supporting ECM synthesis of collagen type II and proteoglycans to preserve articular cartilage integrity.^[40] In bone, CTGF facilitates remodeling by enhancing RANKL-mediated osteoclastogenesis while interacting paracrine with osteoblasts during endochondral ossification, ensuring balanced resorption and formation in response to load-bearing demands.^[40] Furthermore, CTGF sequesters latent TGF-β in the pericellular matrix of cartilage, releasing it upon injury to activate Smad2 signaling and maintain joint homeostasis, with its dysregulation linked to altered cartilage thickness under stress.^[41] CTGF exerts anti-inflammatory effects in resolving acute injuries through interactions with reparative macrophage phenotypes. M2-polarized macrophages secrete CTGF, which dampens excessive inflammation and supports tissue resolution via pathways like AKT, ERK1/2, and STAT3.^[42] This facilitates the transition from inflammatory to proliferative phases, reducing cytokine storms and enabling debris clearance in models of soft tissue repair.^[42] In visceral organs, CTGF aids normal fibrosis resolution during liver regeneration following acute injury, such as partial hepatectomy. It is transiently upregulated in hepatocytes and stellate cells to promote proliferation and temporary ECM deposition for structural support, while its subsequent downregulation allows matrix degradation and restoration of architecture without persistent scarring.^[43]

Pathological Implications

Role in Fibrosis

Connective tissue growth factor (CTGF), also known as CCN2, plays a central profibrotic role by acting as a downstream mediator of transforming growth factor-β (TGF-β), promoting myofibroblast differentiation and excessive extracellular matrix (ECM) production, including collagen synthesis, across various fibrotic diseases.^[44]^[45] In fibrotic conditions, CTGF overexpression amplifies TGF-β signaling, leading to persistent fibroblast activation and ECM deposition that replaces functional tissue.^[46] In idiopathic pulmonary fibrosis (IPF), CTGF drives myofibroblast transdifferentiation in lung fibroblasts and alveolar epithelial cells, resulting in aberrant collagen accumulation and lung remodeling.^[44] Similarly, in systemic sclerosis (SSc), elevated CTGF levels in dermal and pulmonary fibroblasts enhance TGF-β-induced collagen synthesis, contributing to skin thickening and interstitial lung disease.^[47] In liver cirrhosis, CTGF mediates hepatic stellate cell activation downstream of TGF-β, promoting excessive ECM deposition and progression to fibrosis.^[48] CTGF contributes to renal fibrosis in chronic kidney disease by exacerbating podocyte injury and promoting glomerular matrix expansion, leading to progressive nephron loss and impaired filtration.^[49] In podocytes, CTGF overexpression induces ECM proteins like fibronectin and collagen IV, worsening glomerular sclerosis.^[50] In cardiac fibrosis associated with heart failure, CTGF acts as an autocrine regulator in cardiac fibroblasts, increasing collagen deposition that enhances myocardial stiffness and predisposes to arrhythmogenesis by disrupting electrical conduction.^[51] Inhibition of CTGF reduces post-infarction fibrosis, improves left ventricular function, and attenuates remodeling in heart failure models.^[52] Therapeutic strategies targeting CTGF have shown promise in fibrotic disorders, particularly through monoclonal antibodies that block its activity. Pamrevlumab (FG-3019), an anti-CTGF antibody, demonstrated safety and potential efficacy in slowing forced vital capacity decline in phase II trials for IPF; however, phase III trials (ZEPHYRUS-1 and ZEPHYRUS-2) did not meet their primary endpoints, resulting in discontinuation of its development for IPF.^[53]^[54]^[4] Preclinical studies also support anti-CTGF approaches for attenuating skin fibrosis in SSc models and reducing ECM accumulation in hepatic and renal fibrosis.^[47]^[55] Ongoing clinical evaluations continue to explore CTGF inhibition to halt fibrosis progression in multi-organ diseases.^[56]

Role in Cancer and Other Diseases

Connective tissue growth factor (CTGF), also known as CCN2, plays a multifaceted role in cancer pathogenesis, exhibiting both tumor-suppressive and tumor-promoting effects depending on the disease stage and context. In early-stage cancers, CTGF can inhibit cell proliferation, such as in fibroblasts, thereby acting as a suppressor; for instance, high CTGF expression in early ovarian cancer correlates with prolonged patient survival, while in colorectal and lung cancers, elevated levels are associated with reduced malignancy.^[57] However, in advanced stages, CTGF promotes oncogenesis and progression across various malignancies. In breast cancer, CTGF drives tumor cell invasion and migration, contributing to a worse prognosis.^[58] Similarly, in pancreatic cancer, it exacerbates desmoplasia by fostering tumor-stroma interactions, while in hepatocellular carcinoma, increased CTGF expression is linked to metastasis and poor outcomes.^[59]^[57] CTGF facilitates tumor stroma formation, angiogenesis, and metastasis primarily through integrin signaling pathways. It interacts with integrins such as αvβ3 and α5β1 on tumor and stromal cells, promoting extracellular matrix remodeling and epithelial-mesenchymal transition (EMT), which enable metastatic dissemination in cancers like breast and pancreatic.^[57] For angiogenesis, CTGF enhances endothelial cell survival and tube formation, partly by binding vascular endothelial growth factor (VEGF) to amplify vascularization in the tumor microenvironment.^[57] These mechanisms underscore CTGF's potential as a therapeutic target, with inhibitors showing promise in preclinical models of pancreatic and breast cancers to disrupt stroma-tumor crosstalk and halt progression.^[60] Beyond cancer, CTGF contributes to vascular endothelial dysfunction in diabetic complications, particularly nephropathy and retinopathy. In diabetic nephropathy, elevated CTGF levels under hyperglycemic conditions interact with TGF-β to promote glomerular endothelial injury, inflammation, and increased vascular permeability, leading to proteinuria and renal damage.^[61] In diabetic retinopathy, CTGF upregulation amplifies oxidative stress and VEGF-mediated effects, impairing the blood-retinal barrier and inducing pericyte loss, which precedes clinical vascular leakage and neovascularization.^[62] Plasma CTGF is significantly higher in diabetic patients with retinopathy compared to those without, highlighting its biomarker potential.^[63] In osteoarthritis (OA), CTGF exacerbates disease progression by enhancing chondrocyte apoptosis and synovial inflammation. It activates the TGF-β1/CTGF/p38 MAPK pathway in chondrocytes, increasing apoptosis in response to IL-1β stimulation and contributing to cartilage degradation.^[64] Concurrently, CTGF induces synovial fibroblast production of inflammatory cytokines like IL-6 via integrin αvβ5 and NF-κB signaling, promoting chronic inflammation and joint effusion.^[65] Emerging evidence links CTGF to neurodegeneration in Alzheimer's disease through modulation of amyloid-β (Aβ) pathology; elevated CTGF in AD brains, particularly near Aβ plaques, promotes amyloid neuropathology as a downstream effector of insulin resistance, potentially worsening plaque burden and neuronal damage.^[66]^[67]

References

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Connective Tissue Growth Factor: From Molecular Understandings ...
CTGF is a key signaling and regulatory molecule involved in different biological processes, such as cell proliferation, angiogenesis, and wound healing.
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Connective Tissue Growth Factor: A Cysteine-Rich Mitogen ...
A 38-kD cysteine-rich secreted protein which we show to be the major PDGF-related mitogen secreted by human vascular endothelial cells.Missing: discovery | Show results with:discovery
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CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration ...
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### Summary of CTGF Gene (Gene ID: 1490)
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UniProt
Insufficient relevant content. The provided URL content only includes a confirmation prompt, cookie notice, privacy policy link, and help link, with no specific information on the CTGF (CCN2) protein.
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Rating 5.0 (1) · $45 deliveryConnective Tissue Growth Factor (CTGF), also known as CCN2, is a 36-38 kDa member of the CCN (CYR61/CTGF/NOV) family of secreted matricellular proteins (1).Missing: UniProt precursor length
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CTGF is a central mediator of tissue remodeling and fibrosis and its ...
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Connective tissue growth factor (CTGF; now often referred to as CCN2) is a secreted protein predominantly expressed during development, ...Missing: oligomerization | Show results with:oligomerization
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Multifunctional regulatory protein connective tissue growth factor ...
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At the N-terminal, CTGF consists of a signal peptide followed by four major structural domains, including insulin-like growth factor binding protein (IGFBP), ...