Immunocytochemical Localization and Serologic Detection of Transforming Growth Factor β1

Higley, Howard R.; Persichitte, K.; Chu, Skw; Waegell, Wendy; Vancheeswaran, Rama; Black, Carol M.

doi:10.1002/art.1780370218

Cited by 155 publications

(47 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…43). In skin of scleroderma patients, scarring expands outward from the established lesion driven by a wave of inflammation, accompanied by an increased local TGF␤ concentration (44). Given the results presented in this study, we would expect that in this context CCN2 would enhance TGF␤ activation of FAK/Akt contributing to the expansion of the fibrotic lesion.…”

Section: Discussionmentioning

confidence: 68%

CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-β1 in Embryonic Fibroblasts

Stanton

Kennedy

et al. 2006

Journal of Biological Chemistry

146

144

View full text Add to dashboard Cite

CCN2 is induced by transforming growth factor-␤ (TGF␤) in fibroblasts and is overexpressed in connective tissue disease. CCN2 has been proposed to be a downstream mediator of TGF␤ action in fibroblasts; however, the role of CCN2 in regulating this process unclear. By using embryonic fibroblasts isolated from ccn2؊/؊ mice, we showed that CCN2 is required for a subset of responses to TGF␤. Affymetrix genome-wide expression profiling revealed that 942 transcripts were induced by TGF␤ greater than 2-fold in ccn2؉/؉ fibroblasts, of which 345 were not induced in ccn2؊/؊ fibroblasts, including pro-adhesive and matrix remodeling genes. Whereas TGF␤ properly induced a generic Smad3-responsive promoter in ccn2؊/؊ fibroblasts, TGF␤-induced activation of focal adhesion kinase (FAK) and Akt was reduced in ccn2؊/؊ fibroblasts. Emphasizing the importance of FAK and Akt activation in CCN2-dependent transcriptional responses to TGF␤ in fibroblasts, CCN2-dependent transcripts were not induced by TGF␤ in fak؊/؊ fibroblasts and were reduced by wortmannin in wild-type fibroblasts. Akt1 overexpression in ccn2؊/؊ fibroblasts rescued the TGF␤-induced transcription of CCN2-dependent mRNA. Finally, induction of TGF␤-induced fibroblast adhesion to fibronectin and type I collagen was significantly diminished in ccn2؊/؊ fibroblasts. Thus in embryonic fibroblasts, CCN2 is a necessary cofactor required for TGF␤ to activate the adhesive FAK/Akt/phosphatidylinositol 3-kinase cascade, FAK/Akt-dependent genes, and adhesion to matrix.Growth factors intimately contribute to the normal wound healing process, regulating chemotaxis, cell proliferation, neovascularization, and extracellular matrix (ECM) 3 synthesis. CCN2 (connective tissue growth factor), a member of the CCN family of proteins, contains 38 conserved cysteine-rich residues and a heparin-binding domain and is chemotactic and mitogenic for connective tissue cells (1-4). However, the physiological role of CCN2 is largely unknown.As an initial approach to elucidate the physiological function of CCN2, mice deleted for the ccn2 gene were recently generated (5). Mice homozygous for a deletion of the ccn2 gene die soon after birth, displaying an inability of the rib cage to ossify properly (5). The phenotype of these mice is consistent with a role for CCN2 in matrix synthesis and remodeling as ccn2Ϫ/Ϫ embryos show reduction in the expression of bone-specific matrix proteins, such as aggrecan (5). We recently found that embryonic fibroblasts isolated from ccn2Ϫ/Ϫ mice showed reduced basal adhesive signaling, including a reduction of FAK and ERK phosphorylation and delays in ␣-smooth muscle actin (␣-SMA) stress fiber formation (6), suggesting that CCN2 plays a key role in mediating the formation of attachments between the cell and matrix at focal adhesions.Although CCN2 was discovered over a decade ago, the precise biological function of CCN2 has remained elusive. CCN2 is expressed in mesenchymal cells in development, is induced during wound healing (4,8), and is overexpressed in fibrosis (7-11)....

show abstract

Section: Discussionmentioning

confidence: 68%

CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-β1 in Embryonic Fibroblasts

Stanton

Kennedy

et al. 2006

Journal of Biological Chemistry

146

144

View full text Add to dashboard Cite

show abstract

“…Among them, transforming growth factor β (TGF-β) may be one of the implicated cytokines since it induces fibrosis in vivo and stimulates collagen formation in vitro [16]. Furthermore, TGF-β expression in skin of SSc increases at the earliest stages of the disease [17]. In our case, skin sclerosis was prominent at the sites where a subcutaneous tumor was present.…”

Section: Discussionmentioning

confidence: 80%

Systemic Sclerosis Revealing T-Cell Lymphoma

et al. 1999

View full text Add to dashboard Cite

We describe a case of systemic sclerosis (SSc) occurring together with malignant lymphoma. A 43-year-old man, who had noticed sclerodactyly 1 month before consultation, was admitted for progressive skin sclerosis on his forearms and chest. SSc was diagnosed. Immediately after admission, skin sclerosis rapidly extended to the neck and trunk, and subcutaneous tumors developed on the neck, chest and back. Skin sclerosis was prominent at the sites where subcutaneous tumors were present. The tumors were diagnosed as non-Hodgkin’s lymphoma of T-cell phenotype derived from soft tissue. Following 4 cycles of chemotherapy, he had complete remission and the skin sclerosis remarkably improved. It is possible that cytokines produced by T-cell lymphoma cells were responsible for the development of skin sclerosis in this case.

show abstract

“…For example, recent reports localized TGF␤ mRNA to the leading edge of the scleroderma lesion, that is the region of enhanced inflammatory response presumably involved with the initiation of the fibrotic response, but not in the lesional area itself (9,56,57). This is in contrast to CTGF whose expression patterns and levels are highly correlated with the severity of fibrosis (44,58).…”

Section: Ctgf Expression In Scleroderma Fibroblastsmentioning

confidence: 99%

CTGF and SMADs, Maintenance of Scleroderma Phenotype Is Independent of SMAD Signaling

Holmes

Abraham

et al. 2001

Journal of Biological Chemistry

391

437

View full text Add to dashboard Cite

In normal adult fibroblasts, transforming growth factor-␤ (TGF␤) induces the expression of connective tissue growth factor (CTGF). CTGF independently promotes fibroblast proliferation and matrix deposition, and in acute models of fibrosis promotes cell proliferation and collagen deposition acting synergistically with TGF␤. In contrast to normal fibroblasts, fibroblasts cultured from fibrotic tissues express high basal levels of CTGF, even in the absence of added TGF␤. Induction of transcription by TGF␤ requires the action of SMAD proteins. In this report we have investigated the role of SMADs in the TGF␤-induction of CTGF in normal fibroblasts and in the elevated levels of CTGF expression found in dermal fibroblasts cultured from lesional areas of patients with scleroderma, a progressive fibrotic disorder that can affect all organs of the body. We have identified a functional SMAD binding site in the CTGF promoter. TGF␤-induction of CTGF is dependent on SMAD3 and SMAD4 but not SMAD2 and is p300-independent. However, mutation of the SMAD binding site does not reduce the high level of CTGF promoter activity observed in dermal fibroblasts cultured from lesional areas of scleroderma patients. Conversely, the previously termed TGF␤RE in the CTGF promoter is required for basal CTGF promoter activity in normal fibroblasts and for the elevated level of CTGF promoter activity in scleroderma fibroblasts. Thus, the maintenance of the fibrotic phenotype in scleroderma fibroblasts, as visualized by excess CTGF expression, appears to be independent of SMAD-dependent TGF␤ signaling. Furthermore, given CTGF's activities, the high level of CTGF expression observed in scleroderma lesions may contribute to the excessive scarring observed in this disorder.

show abstract

Immunocytochemical Localization and Serologic Detection of Transforming Growth Factor β1

Cited by 155 publications

References 22 publications

CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-β1 in Embryonic Fibroblasts

CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-β1 in Embryonic Fibroblasts

Systemic Sclerosis Revealing T-Cell Lymphoma

CTGF and SMADs, Maintenance of Scleroderma Phenotype Is Independent of SMAD Signaling

Contact Info

Product

Resources

About