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.

published_or_final_version / abstract / toc / Pharmacology / Master / Master of Philosophy

The composition of orthopaedic wear testing lubricants used to mimic synovial fluid (SF) is known to significantly affect in vitro polyethylene (PE) wear; however, some wear testing standards may be promoting the use of lubricants that are not clinically relevant. The present thesis evaluated the biochemical composition of human osteoarthritic and periprosthetic SF in order to propose changes to lubricant specifications in current wear testing standards. Using this data, pin-on-disc wear tests were conducted to explore the effects of more clinically relevant lubricants on PE wear. Results showed that wear decreased using a more clinically relevant lubricant. Samples of these lubricants were biochemically evaluated and compared to the SF results previously obtained, which showed that current standards for wear testing lubricants are biochemically different from SF. The findings from the present thesis encourage the modification of standardized lubricant specifications to improve wear testing protocols and guarantee clinically relevant wear testing.

The composition of orthopaedic wear testing lubricants used to mimic synovial fluid (SF) is known to significantly affect in vitro polyethylene (PE) wear; however, some wear testing standards may be promoting the use of lubricants that are not clinically relevant. The present thesis evaluated the biochemical composition of human osteoarthritic and periprosthetic SF in order to propose changes to lubricant specifications in current wear testing standards. Using this data, pin-on-disc wear tests were conducted to explore the effects of more clinically relevant lubricants on PE wear. Results showed that wear decreased using a more clinically relevant lubricant. Samples of these lubricants were biochemically evaluated and compared to the SF results previously obtained, which showed that current standards for wear testing lubricants are biochemically different from SF. The findings from the present thesis encourage the modification of standardized lubricant specifications to improve wear testing protocols and guarantee clinically relevant wear testing.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 8 uppsatser.

Thesis (M.S.)--University of Missouri--Columbia, 2004. / "July 2004." Typescript. Includes bibliographical references (leaves 63-70). Also issued on the Internet. Also available on the Internet.