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First published online 18 May 2004
doi: 10.1242/jcs.01112

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.01112v1 jcs.01112v2 117/13/2731    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oshima, Y. Articles by Shukunami, C. Search for Related Content PubMed PubMed Citation Articles by Oshima, Y. Articles by Shukunami, C.

Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I

¹ Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
² Department of Ophthalmology, Osaka University Medical School, Suita 565-0871, Japan
³ Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Suita 565-0871, Japan

^* Author for correspondence (e-mail: shukunam{at}frontier.kyoto-u.ac.jp)

Accepted 20 January 2004

Tenomodulin (TeM) is a type II transmembrane glycoprotein that contains a C-terminal domain with homology to the mature, secreted form of chondromodulin-I (ChM-I), a cartilage-derived angiogenesis inhibitor. TeM transcripts have been found in hypovascular tissues such as tendons and ligaments but the biological activity of TeM has not yet been fully explored. Using an adenovirus expression system, we utilized the forced expression and subsequent secretion of the human TeM C-terminal 116 amino acids (Ad-shTeM) in human umbilical vein endothelial cells (HUVECs) to assess the anti-angiogenic properties of TeM. The C-terminal 120 amino acids of the human ChM-I precursor (Ad-shChM-I) was similarly expressed in HUVECs as a comparison study. Transduction of both Ad-shTeM and Ad-shChM-I resulted in significant impairment of the tube-forming activity of HUVECs, when cultured in Matrigel. Similarly, conditioned medium from COS7 cells, transfected with plasmid DNA encoding shTeM or shChM-I, inhibited tube formation of HUVECs when compared to medium derived from either COS7 cells transfected with control vector or from non-transfected cells.

Upon infection of HUVECs with Ad-shTeM or Ad-shChM-I, DNA synthesis stimulated by vascular endothelial growth factor (VEGF) was reduced to 40-50% of normal levels. Additionally, in a modified Boyden chamber assay, migration of HUVECs in response to VEGF was significantly affected following transduction of either Ad-shTeM or Ad-shChM-I and these transduced HUVECs were found to spread well on type I collagen or fibronectin, but not on vitronectin. Furthermore, the transduction of either Ad-shTeM or Ad-shChM-I in human melanoma cells resulted in suppression of tumor growth in association with decreased vessel density in vivo. Hence, we have demonstrated that, similarly to ChM-1, the C-terminal domain of TeM exhibits both anti-angiogenic and anti-tumor activities when expressed in a secreted form.

Key words: Angiogenesis inhibitor, Tenomodulin, Chondromodulin-I, Tendon

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