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TGF-alpha and ErbB2 production in synovial joint tissue: increased expression in arthritic joints
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2005 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, Vol. 34, no 3, 204-211 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Cell types present in synovial joint tissues and during synovitis are known to produce epidermal growth factor receptor (EGFR)/ErbB-1/HER-1 and the potent EGFR-ligand transforming growth factor-alpha (TGF-) in vitro. Concomitant expression of TGF-, EGFR, and ErbB2 gives a strong proliferative drive in vitro and in vivo. However, the presence of TGF- and members of the EGFR/EGFR-ligand family has not been thoroughly investigated in joint tissue in vivo. We aimed to determine whether TGF-, EGFR, and ErbB2 are present in human synovial joints, especially during rheumatoid arthritis (RA).

Methods: TGF- protein was immunodetected in knee synovial fluid (SF) collected from 23 RA patients, eight patients with other arthritic conditions, two osteoarthritis (OA) patients, and six post-traumatic patients (control). TGF- mRNA and TGF-, ErbB2, EGFR, and CD68 immunoreactivity were detected in knee synovial biopsies (6 RA/2 OA/6 control) using in situ hybridization and immunohistochemistry. TGF- mRNA was determined in SF cells by reverse transcription polymerase chain reaction (RT-PCR) and/or the Northern blot technique.

Results: TGF- protein was found in the synovial membrane (SM) and in the majority of SF samples. TGF- levels were significantly higher (p<0.001) in SF of RA patients than controls, TGF- protein and mRNA were increased and more widespread in SM of RA patients. In addition, white blood cells collected from RA SF expressed TGF- mRNA. Immunoreactivity for ErbB2 was found in SM and was more widespread in RA patients than in controls.

Conclusion: The presence of TGF- in normal SF and SM may indicate a physiological maintenance function. The increased expression of TGF- and ErbB2 in RA SF and SM may give rise to an abnormal growth pattern, contributing to inflammatory synovial hyperplasia.

Place, publisher, year, edition, pages
2005. Vol. 34, no 3, 204-211 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-12780DOI: 10.1080/03009740510017715OAI: diva2:17033
Available from: 2007-11-22 Created: 2007-11-22 Last updated: 2009-05-15
In thesis
1. Studies of transforming growth factor alpha in normal and abnormal growth
Open this publication in new window or tab >>Studies of transforming growth factor alpha in normal and abnormal growth
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regulation of growth is of fundamental importance for development of the organism and to maintain health. The induction of cell proliferation and matrix production are influenced by several different signaling systems, most importantly by growth factors.

The human HER-family of growth factor ligands and receptors is one of the most studied and, at present, one of the most complex including 4 tyrosine kinase receptors and at least 11 different ligands cooperating in the transfer of signals. The HER-family growth responses are also influenced by other intercellular and extracellular signals, including matrix components, cytokines and hormones mediating e.g. inflammation.

HER-1 (EGFR) is one of the best known and most extensively studied growth factor receptors. TGF-alpha is possibly the most potent HER-1 ligand and influences wound healing, epidermal maintenance, gastrointestinal function, lactation, pulmonary function and more. Several studies have shown important regulatory functions for some inflammatory cytokines on TGF-alpha production in white blood cells. HER-1 is widespread in epithelial cells but also in mesenchymal cells such as fibroblasts, osteogenic and chondrogenic cells. Consequently, many tumors arising from these cell types express HER family members and often show TGF-alpha and/or HER activation. Indeed, mammary cancer development has been shown when over expressing both TGF-alpha and HER-2 in mouse mammary cells in vivo.

In recent years the first HER-1 and HER-2 inhibitors have come into clinical practice for treatment of breast cancer, lung cancer and gastrointestinal cancers, sometimes with great success. However, more knowledge is needed concerning the inflammatory regulation of HER-family expression including where and how the ligands and receptors cooperate. Therefore we were interested in studying the role of TGF-alpha in normal and abnormal growth.

First we showed that the acute inflammatory cytokine IL-6 regulates TGF-alpha expression in U-937-1 monocytoid cells. Secondly, we detected a possible long-term enhancing influence of singledose UVR on HER-1 expression in normal human melanocytes. We continued thirdly by revealing TGF-alpha production concomitant with HER-2 in normal human synovia and release of soluble TGF-alpha into the synovial fluid. Both TGF-alpha and HER-2 production were significantly increased in inflammatory joint conditions, e.g. RA. Fourthly, we demonstrated expression of TGF-alpha, HER-1 and HER-2 in synovial sarcoma cells in culture; the observed HER-2 phosphorylation was dependent on ligand induced HER-1 activation.

The presented results indicate that TGF-alpha expression can be enhanced by acute inflammatory cytokine IL-6, possibly contributing to growth stimulatory effects assigned to IL-6 itself.

The acute effects of UVR on melanocytes mediate up-regulated steady-state expression of HER-1, constituting a potential target for locally produced TGF-alpha that may induce melanocyte proliferation.

TGF-alpha and HER-2 seem to have a role in the maintenance of

synovial joint tissues. Upregulation of TGF-alpha and HER-2 in inflammatory joint conditions, e.g. RA, represents a novel mechanism for synovial proliferation contributing to joint deterioration.

TGF-alpha, HER1 and HER-2 may have a role in synovial sarcoma proliferation; further investigation is needed to evaluate HER-family inhibitors as a possible treatment alternative in this type of cancer.

Place, publisher, year, edition, pages
Institutionen för klinisk och experimentell medicin, 2007
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1025
TGF-alpha, HER, EGFR, synovia, synovial sarcoma, RA, synovitis
National Category
Cell and Molecular Biology
urn:nbn:se:liu:diva-10286 (URN)978-91-85895-61-8 (ISBN)
Public defence
2007-11-23, Berzeliussalen, Ing 64, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2007-11-22 Created: 2007-11-22 Last updated: 2009-08-22

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