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The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis.
Arthritis Rheum. 2010 Jan; 62(1):280-90.AR

Abstract

OBJECTIVE

Fra-2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra-2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra-2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra-2 induces fibrosis.

METHODS

Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra-2-transgenic and wild-type mice. The expression of Fra-2 in SSc patients and in animal models of SSc was analyzed by real-time polymerase chain reaction and immunohistochemistry. Fra-2, transforming growth factor beta (TGFbeta), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small-molecule inhibitors.

RESULTS

Fra-2-transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra-2 was up-regulated in SSc patients and in different mouse models of SSc. Stimulation with TGFbeta and platelet-derived growth factor (PDGF) significantly increased the expression of Fra-2 in SSc fibroblasts and induced DNA binding of Fra-2 in an ERK-dependent manner. Knockdown of Fra-2 potently reduced the stimulatory effects of TGFbeta and PDGF and decreased the release of collagen from SSc fibroblasts.

CONCLUSION

We demonstrate that Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFbeta and PDGF. Since transgenic overexpression of Fra-2 causes not only fibrosis but also vascular disease, Fra-2 might be an interesting novel candidate for molecular-targeted therapies for SSc.

Authors+Show Affiliations

University of Erlangen-Nuremberg, Erlangen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20039427

Citation

Reich, Nicole, et al. "The Transcription Factor Fra-2 Regulates the Production of Extracellular Matrix in Systemic Sclerosis." Arthritis and Rheumatism, vol. 62, no. 1, 2010, pp. 280-90.
Reich N, Maurer B, Akhmetshina A, et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum. 2010;62(1):280-90.
Reich, N., Maurer, B., Akhmetshina, A., Venalis, P., Dees, C., Zerr, P., Palumbo, K., Zwerina, J., Nevskaya, T., Gay, S., Distler, O., Schett, G., & Distler, J. H. (2010). The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis and Rheumatism, 62(1), 280-90. https://doi.org/10.1002/art.25056
Reich N, et al. The Transcription Factor Fra-2 Regulates the Production of Extracellular Matrix in Systemic Sclerosis. Arthritis Rheum. 2010;62(1):280-90. PubMed PMID: 20039427.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. AU - Reich,Nicole, AU - Maurer,Britta, AU - Akhmetshina,Alfiya, AU - Venalis,Paulius, AU - Dees,Clara, AU - Zerr,Pawel, AU - Palumbo,Katrin, AU - Zwerina,Jochen, AU - Nevskaya,Tatiana, AU - Gay,Steffen, AU - Distler,Oliver, AU - Schett,Georg, AU - Distler,Jörg H W, PY - 2009/12/30/entrez PY - 2009/12/30/pubmed PY - 2010/3/12/medline SP - 280 EP - 90 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 62 IS - 1 N2 - OBJECTIVE: Fra-2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra-2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra-2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra-2 induces fibrosis. METHODS: Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra-2-transgenic and wild-type mice. The expression of Fra-2 in SSc patients and in animal models of SSc was analyzed by real-time polymerase chain reaction and immunohistochemistry. Fra-2, transforming growth factor beta (TGFbeta), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small-molecule inhibitors. RESULTS: Fra-2-transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra-2 was up-regulated in SSc patients and in different mouse models of SSc. Stimulation with TGFbeta and platelet-derived growth factor (PDGF) significantly increased the expression of Fra-2 in SSc fibroblasts and induced DNA binding of Fra-2 in an ERK-dependent manner. Knockdown of Fra-2 potently reduced the stimulatory effects of TGFbeta and PDGF and decreased the release of collagen from SSc fibroblasts. CONCLUSION: We demonstrate that Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFbeta and PDGF. Since transgenic overexpression of Fra-2 causes not only fibrosis but also vascular disease, Fra-2 might be an interesting novel candidate for molecular-targeted therapies for SSc. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/20039427/The_transcription_factor_Fra_2_regulates_the_production_of_extracellular_matrix_in_systemic_sclerosis_ L2 - https://doi.org/10.1002/art.25056 DB - PRIME DP - Unbound Medicine ER -