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At least 19 recordsLinked to original sources
PubMed1991

Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.

Human umbilical vein endothelial (HUVE) cells have been previously reported to express the genes for the A and B chains of PDGF and to secrete PDGF-related factors into culture media. Antihuman PDGF IgG affinity chromatography was used to purify PDGF-related activity from HUVE cell-conditioned media. Immunoblot analysis of the affinity-purified proteins with anti-PDGF IgG and antibodies specific for the A or B chain peptides of PDGF combined with chemotactic and mitogenic assays revealed that the major PDGF immunorelated molecule secreted by HUVE cells is a monomer of approximately 36-38 kD and that less than 10% of the purified biologically active molecules are PDGF A or B chain peptides. Screening of an HUVE cell cDNA library in the expression vector lambda gtl 1 with the anti-PDGF antibody resulted in the cloning and sequencing of a cDNA with an open reading frame encoding a 38-kD cysteine-rich secreted protein which we show to be the major PDGF-related mitogen secreted by human vascular endothelial cells. The protein has a 45% overall homology to the translation product of the v-src-induced CEF-10 mRNA from chick embryo fibroblasts. We have termed this new mitogen connective tissue growth factor.

Amino Acid Sequence↗
PubMed1992

Epidermal growth factor accelerates connective tissue wound healing in the perforated rat mesentery.

Epidermal growth factor (EGF) has been reported to stimulate healing of wounds in skin, cornea, and gastric mucosa. In the present study, we further investigate the effect of endogenous and exogenous EGF in healing of connective tissue wounds using the rat perforated mesentery model. Healing of mesenteric perforations is accomplished by the connective tissue fibroblasts since there are no interfering variables such as interactions of epithelial cells, desiccation, or foreign materials such as sutures or subcutaneous implants. We performed laparotomy in 114 adult male Sprague-Dawley rats and made 20 standardized perforations in the mesentery of each rat with a scalpel. Rats were randomly assigned to five groups. Group I received no treatment after surgery; Group II received intraperitoneal injections of phosphate-buffered saline (PBS) after surgery and then twice daily for the following 3 days; Group III received 10 micrograms of EGF in the PBS injections according to the same regimen as Group II; Group IV had sham exploration of the submandibular salivary glands; and Group V animals had excision of the submandibular glands 3 days before laparotomy to deprive the main source of EGF in rat. On Days 4 through 10 after surgery rats were sacrificed and the percentage of perforations in each rat which were closed was determined. The curves for the time course of wound closure for Groups IV and V were not different indicating that endogenous submandibular EGF does not play a role in healing of mesenteric wounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Fibroblast growth factors in connective tissue disease associated interstitial lung disease.

Fibrosis is a major cause of morbidity and mortality in chronic inflammatory diseases, especially interstitial pulmonary disorders. Fibroproliferation is an important part of this fibrotic response, and is mediated largely through growth factors such as platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) I and tumour necrosis factor-alpha (TNF-alpha). Although there is some evidence implicating these cytokines in fibrotic disorders, strong evidence in vivo is almost nonexistent. In order to ascertain the role that these factors play in inflammatory lung disorders associated with connective tissue diseases, alveolar mononuclear cells have been obtained from subjects by bronchoalveolar lavage and assessed for the spontaneous release of fibroblast growth factors. The study population consisted of subjects with a variety of different connective tissue disorders, both with and without inflammatory pulmonary complications. It was found that lavage cells spontaneously secreted fibroblast growth factor activity over 24 h with maximum activity detected at 6 to 12 h. Growth factor activity could be detected in most subjects with connective tissue disease-associated inflammatory lung disease and some normal subjects, but the amount of growth factor activity was much higher in the former than in the latter. By means of antibody depletion experiments all growth factor activity from lavage cells of normal patients was attributable to TNF-alpha while patients with interstitial lung disease secreted large amounts of PDGF and fibronectin in addition to TNF-alpha. Approximately 40-50% of the total released growth factor activity could be accounted for by PDGF, and 100% by the combination of PDGF, TNF-alpha and fibronectin. While TNF-alpha is released from the bronchoalveolar lavage cells of many subjects, in addition, many patients with interstitial lung disease also release spontaneously, large amounts of fibroblast growth factor activity attributable to PDGF and fibronectin.

Bronchoalveolar Lavage Fluid↗
PubMed2026

SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear. OBJECTIVE: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME. DESIGN: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways. RESULTS: We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis. CONCLUSIONS: Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Humans↗
PubMed2026

CTGF/CCN2 Promotes Invasive Growth in Cervical Cancer Spheroids and Is Associated With Metastatic Cervical Cancer Tissue.

BACKGROUND/AIM: Metastatic spread defines the lethality of cervical cancer (CC). Connective tissue growth factor (CTGF/CCN2) regulates cell- extracellular matrix interactions but its role in CC is not well-defined. This study investigates the role of CTGF in driving CC invasive growth and its prevalence in patient tissues. MATERIALS AND METHODS: CC spheroids (C33A, HT3) were treated with recombinant human CTGF (rhCTGF) or a function-blocking antibody (IgG CTGF). Invasive growth was assessed via 3D spheroid assay using a Celigo imaging cytometer. Cancer stem cell (CD133, CD44) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin) were analyzed by immunofluorescence. CTGF expression was evaluated using a tissue microarray containing 69 cases in triplicate from pre-invasive, invasive (FIGO I-III), and metastatic cervical lesions, quantified via immunofluorescence scoring. RESULTS: Functional blockade of CTGF significantly reduced 3D spheroid invasive growth in C33A and HT3 cells (p<0.0001). Immunofluorescence revealed that CTGF modulation altered spatial distribution of key proteins: rhCTGF induced surface clustering of CD133 and peripheral N-cadherin enrichment, while CTGF blockade was associated with apparent nuclear/perinuclear enrichment of CD133 and E-cadherin and reduced N-cadherin signal. In patient tissue cores, metastatic samples exhibited the highest CTGF fluorescence intensity. High CTGF expression [immunoreactivity score (IRS) &#x2265; 6] was most prevalent in FIGO stage I (35.5%) compared to stage III (10.0%). Kaplan-Meier analysis revealed that high CTGF mRNA expression was associated with significantly reduced recurrence-free survival (log-rank p=0.0032). CONCLUSION: In 3D models of CC, CTGF appears to regulate an invasive phenotype, presumably by controlling aberrant localization of stemness and EMT markers. Its apparently elevated expression in early-stage cervical carcinomas and metastases, combined with its prognostic value for recurrence-free survival, suggests that CTGF may be involved in triggering the potential for metastasis and could therefore serve as an early prognostic biomarker.

Humans↗
PubMed1992

Physical mapping of human loci homologous to the chicken nov proto-oncogene.

The human locus (novH) corresponding to the nov protooncogene overexpressed in avian nephroblastoma has been identified and mapped on chromosome 8q24.1. Another locus sharing homology with novH and corresponding to the connective tissue growth factor (CTGF) gene has also been mapped on chromosome 6q23.1. The chromosomal assignment of nov and CTGF proximal to c-myc and c-myb respectively is of interest because chromosomal abnormalities involving these regions have been associated with different human tumors including Wilms'.

Animals↗
PubMed1992

Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development.

cyr61 is a growth factor-inducible immediate early gene initially identified in serum-stimulated mouse fibroblasts. It encodes a member of an emerging family of cysteine-rich secreted proteins that includes a connective tissue growth factor. We show here that cyr61 is expressed in the developing mouse embryo and extraembryonic tissues. In the placenta, cyr61 is expressed in regions of trophoblastic origin, including the ectoplacental cone and the trophoblastic giant cells. In the midgestation embryo, cyr61 is expressed in the smooth muscle vessel walls of the arterial circulatory system. Most notably, expression is found in developing cartilaginous elements, including the limbs, ribs, and prevertebrae. In addition, regions of the chondrocranium and craniofacial elements, such as Meckel's cartilage, also express cyr61. Thus, cyr61 transcript is found in mesenchymal cells of both mesodermal and ectodermal origin during their differentiation into chondrocytes. The temporal and spatial regulation of cyr61 expression and the biochemical features of its encoded protein suggest that cyr61 may be important for the normal growth, differentiation, or morphogenesis of the cartilaginous skeleton of the embryo.

Amino Acid Sequence↗
PubMed2026

Severe Phenotype in an Indian Family With Progressive Pseudorheumatoid Arthropathy of Childhood.

Progressive pseudorheumatoid arthropathy of childhood (PPAC) is a rare autosomal recessive progressive condition that affects the cartilage of joints and bones. The symptoms of PPAC include stiffness of the joints, bony swelling of the toes and fingers, short stature, kyphosis, and muscle weakness. The radiologic manifestations are often mistaken for juvenile rheumatoid arthritis and include platyspondyly, widened metaphyses, flattened epiphyses, and large femoral heads. The disease is caused by variants in the WISP3 (also known as CCN6) gene, which encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. We describe three affected female siblings in an Indian family with PPAC, all of whom manifest a severe phenotype of the disease. The girls all walked with a crouching gait from severe joint contractures. Radiographic findings included generalized periarticular osteopenia and widened metaphyses. The radiographs of the hands and feet showed similar changes with narrow joint spaces, widened metaphyses, and flattened epiphyses. Elbows and knees revealed gracile bones, and contractures with severe muscle atrophy. Spine films were significant for marked beaking, lumbar vertebrae anterior narrowing, irregular end plates and rotational scoliosis. X-rays of the hips revealed deformed femurs, coxa vara, and large flat epiphyses. All affected individuals were compound heterozygotes for two pathogenic variants in the WISP3/CCN6 gene, a novel nonsense variant (c.172A>T [p.Lys58*]) and a 2-base pair deletion (c.740_741delGT [p.Cys247Leufs*31]). This combination of a nonsense and frameshift variant has not previously been reported and may be the explanation for the severe clinical manifestation of PPAC in this family. Further investigation into the mechanism of the disease may provide promising therapies to modify disease progression.

WISP3↗
PubMed2026

Participation of the purinergic P2X7 receptor in molecular complexes in the nucleus of human chondrocytes.

In addition to the purinergic receptor P2X7R's known activity as a sensor of damage-associated molecular patterns (DAMPs), evidences support its role in maintaining tissue homeostasis. Its presence in cellular compartments other than its usual transmembrane localization suggests its involvement in specific signaling pathways. This study aimed to analyze P2X7R in the nucleus of human chondrocytes and search for potential interacting partners. Through co-immunoprecipitation and proximity ligation assay we discovered that, independent of extracellular ATP levels, P2X7R is abundantly present in both the nuclear membrane and in the nucleoplasm, where it is found in close proximity to lamin A/C (a component of the nuclear lamina), emerin (a protein involved in the assembly and disassembly of the nuclear envelope), and SUN2 (an inner nuclear membrane protein that facilitates the transmission of mechanical forces). Furthermore, chromatin immunoprecipitation revealed the participation of P2X7R in molecular complexes located in the promoter of specific genes including Sox9, TRPS1, FOXO3a, integrin &#x3b2;2 and connective tissue growth factor. Overall, this evidence reveals for the first time novel partners of P2X7R that place it in an intricate network that influences nuclear structure, mechanosensitivity, chromatin organization, and gene expression. Specifically, on the one hand, a close association between P2X7R and nuclear proteins participating in the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex (lamin A/C, emerin, and SUN2) places it among the factors involved in mechanosignaling and the maintenance of nuclear integrity; on the other, its recruitment to specific gene promoters suggests that it may act as a transcription regulator.

Humans↗
PubMed1992

Insulin-like growth factor binding protein (IGFBP)4 accounts for the connective tissue distribution of endothelial cell IGFBPs perfused through the isolated heart.

Insulin-like growth factor binding protein 4 (IGFBP4) was purified to homogeneity from conditioned media of bovine pulmonary artery endothelial cells and shown to have the N-terminal amino acid sequence DEAIHCPPCS, a sequence unique to IGFBP4. The IGFBP4 was separated into predominantly glycosylated and nonglycosylated fractions, with each fraction separately perfused through isolated, beating rat hearts. Both forms of IGFBP4 crossed the capillary boundary of the heart and distributed primarily in subendothelial connective tissue components with a connective tissue/cardiac muscle distribution ratio of 20:1 for the glycosylated fraction and 27:1 for the nonglycosylated fraction. Perfused IGFBP1, 2, 3, and IGF-I also crossed the capillary boundary but in contrast to IGFBP4, preferentially localized in cardiac muscle with a connective tissue/muscle ratio of approximately 1:3. We conclude that the connective tissue distribution previously reported for IGFBPs in conditioned media of pulmonary artery endothelial cells is due to IGFBP4.

Amino Acid Sequence↗
PubMed1992

Impairment of osteophyte formation in hyperglycemic patients with type II diabetes mellitus and knee osteoarthritis.

OBJECTIVE: Since insulin is a potent growth factor for connective tissue, the present study was designed to investigate whether radiographic features of knee osteoarthritis (OA) in patients with poorly controlled, insulin-resistant type II diabetes mellitus differ from those in nondiabetic controls with knee OA. METHODS: Radiographs from 25 female patients with diabetes and knee OA were compared with those from 48 female controls who were similar with respect to age, weight, and duration of OA symptoms. RESULTS: Although the 2 groups were similar with respect to the frequency and severity of joint space narrowing, subchondral sclerosis, and geodes, osteophytes were less common in the patients with diabetes (P = 0.044), and spurring, when present, tended to be "marked" less often in the diabetic patients than in the controls. CONCLUSION: The data suggest that diminished availability of insulin at the cellular level or diabetic microvascular disease attenuates the chondro- and osteogenesis required for osteophyte formation in the joints of patients with OA.

Adult↗
PubMed2026

Mismatch repair protein MLH1 controls testis development by regulating the Hippo-YAP signaling pathway.

DNA mismatch repair (MMR) maintains genomic stability, and defects in MMR genes such as MLH1 and MSH2 predispose to cancer. Unlike other MMR components, MLH1 has unexplained roles in development, as Mlh1-deficient male mice exhibit severe testicular hypoplasia and sterility. Here, we uncover that MLH1 regulates testis development through the Hippo-Yes-associated protein (YAP) pathway. MLH1 directly binds YAP via its C-terminal domain and the WW domains of YAP, competitively inhibiting LATS1-mediated YAP phosphorylation. This interaction stabilizes YAP by suppressing ubiquitination and promotes its nuclear translocation dependent on MLH1's nuclear localization signal. Additionally, MLH1 facilitates YAP-TEAD complex formation, enabling expression of testicular development genes, including Wt1, Sox9, and Ctgf. These functions are independent of the MMR activity of MLH1. Mlh1-deficient mice show elevated YAP phosphorylation, reduced target gene expression, and impaired proliferation in developing testes. Pharmacological inhibition of the Hippo pathway kinases MST1/2 partially rescues testis hypoplasia in Mlh1-/- mice. These findings establish MLH1 as a Hippo pathway regulator and resolve its long-standing role in male gonad development.

Male↗
PubMed1992

Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas.

Histological and anatomopathological studies performed on 152 independent myeloblastosis-associated virus type 1 (MAV1)-induced nephroblastomas allowed us to precisely define the chronology of tumor development in chickens. Three tumors representing increasing developmental stages were used to construct genomic libraries and to study both the state of proviral genomes and the sites of MAV1 integration in genomic DNA. We established that increasing levels of proviral rearrangement, eventually leading to the elimination of infectious MAV genomes, were associated with tumor progression and that 22 individual tumors, representative of different developmental stages, did not contain any common MAV1 integration site. Cloning of cellular fragments flanking the MAV1-related proviruses in tumor DNA showed that each one of eight nephroblastomas tested expressed a high level of an as yet unidentified cellular gene (nov) whose transcription is normally arrested in adult kidney cells. Cloning of the normal nov gene established that in one tumor, fused long terminal repeat-truncated nov mRNA species were expressed, indicating that at least in that case, the high level of nov expression was under the control of the MAV long terminal repeat promoter. The normal nov gene encodes a putative 32-kDa secreted polypeptide, which is a member of a new family of proteins likely to be involved in cell growth regulation. We also showed that the expression of an amino-terminal-truncated nov product in chicken embryo fibroblasts was sufficient to induce their transformation.

Amino Acid Sequence↗
PubMed1975

A potent new mesodermal growth factor from mouse submaxillary gland. A quantitative, comparative study with previously described submaxillary gland growth factors.

A new growth factor with potent growth stimulating effects on connective tissue cells of the cornea has been isolated and partially purified from mouse submaxillary glands. A computerized image analysis system has been used to quantitate the growth responses of connective tissue fibroblasts to this new growth factor and to compare its activity with that of four previously described growth factors [nerve growth factor (NGF), epidermal growth factor (EGF), mesodermal growth factor (MGF), and thymocyte-transforming factor (TTF)] also obtained from mouse submaxillary glands. The new factor is as potent a growth stimulator as the previously described MGF. All five of the growth factors possessed esteropeptidase activity (trypsin-like) and general proteolytic activity. There was no correlation between the degree of growth stimulation of the connective tissue cells and either the esteropeptidase or general proteolytic activities of any of the growth factors.

Animals↗
PubMed1979

Platelet alpha granules contain a growth factor for fibroblasts.

Platelets contain a polypeptide growth factor that stimulates the replication of normal connective tissue cells; this platelet-derived growth factor (PDGF) is released during the clotting process. Human platelets from normal volunteers were disrupted by nitrogen cavitation, and the subcellular organelles were fractionated by ultracentrifugation through a 30%--60% sucrose gradient. Electron microscopy revealed that fraction 7 (density 1.23 g/liter) contained the largest number of alpha granules. The specific activity of platelet fibrinogen, an alpha-granule marker, was also highest in this fraction. The subcellular fractions were assay for the presence of PDGF and for beta-thromboglobulin. PDGF was assayed quantitatively by the stimulation of DNA synthesis in confluent growth-arrested BALB/c-3T3 cells, whereas the concentration of beta-thromboglobulin was determined by radioimmunoassay. The highest concentrations of both PDGF and beta-thromboglobulin were found in the alpha-granule fraction. In contrast, beta-glucuronidase, a lysosomal enzyme, was more diffusely distributed and had its highest specific activity in fractions of lower density than those for PDGS, beta-thromboglobulin, or fibrinogen. The data demonstrate that the alpha granules of platelets provide a unique delivery system for PDGF, a polypeptide hormone with growth-promoting activity for connective tissue cells.

Animals↗
PubMed1976

Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton.

A new dominant mutation, tight-skin (Tsk), is located on Chromosome 2, two recombination units distal to pallid (pa). Heterozygotes (Tsk/+) have tight skins with marked hyperplasia of the subcutaneous loose connective tissues, increased growth of cartilage and bone, and small tendons with hyperplasia of the tendon sheaths. In the loose connective tissue there are large accumulations of microfibrils in the intercellular space. In spite of the increased skeletal size, body weight is not increased. Increase in size of the thoracic skeleton is especially pronounced and leads to pathologic distentsion of the hollow thoracic viscera. Concentration of growth hormone in the pituitary and plasma is normal. Homozygotes (Tsk/TSK) die in utero at 7 to 8 days of gestation. We propose the hypothesis that Tsk might act by causing defective cell receptors with high affinity for a somatomedin-like factor promoting growth of cartilage, bone, and connective tissue and low affinity for a multiplication-stimulating factor promoting embryonic growth.

Animals↗
PubMed1992

Angiogenic growth factors: their effects and potential in soft tissue wound healing.

Since their discovery 30 years ago, angiogenic growth factors have been demonstrated to stimulate neovascularization in vitro and in animal studies. Over the last decade, knowledge gained in the field of angiogenic growth factors has grown immensely. These angiogenic growth factors exist in four major families: fibroblast growth factor (FGF), transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF). Each has the ability to induce soft tissue vascularization in microgram quantities. In animal models, FGF, TGF-beta, PDGF, and EGF have been shown to enhance soft tissue wound healing. In human clinical trials, EGF, and a mixture of PDGFs have been demonstrated to accelerate epidermal regeneration in cutaneous wounds. These factors have considerable therapeutic potential in the areas of soft tissue wound healing and otolaryngology. This article reviews important aspects of angiogenic growth factors and discusses their future potential in soft tissue wound healing.

Animals↗