Yusuke Oshima

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

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.

Sequence analysis of zebrafish chondromodulin-1 and expression profile in the notochord and chondrogenic regions during cartilage morphogenesis.

Chondromodulin-I (ChM-I) is suggested in higher vertebrate systems to function as a key regulatory protein for cartilage development. To further understand the process of chondrogenesis and the function of ChM-I, we have cloned the zebrafish cDNA for chondromodulin-1 (chm1) and have mapped the chm1 gene locus. The expression profile of chm1 was determined during zebrafish embryonic development and compared to that of type II collagen (col2a1). Maternal chm1 transcripts were detected before midblastula transition and zygotic expression of chm1 was first observed in the notochord at the 10-somite stage. At later developmental stages, chm1 expression was detected in areas surrounding the otic vesicles, in the developing craniofacial cartilage elements, and in the chondrogenic region of the pectoral fins.

Slope Failures in Analogue Models of Accretionary Wedges

Sandbox models commonly produce slope failures and mass-transport on the top free surface, which can be an analogue for submarine slides. We have been conducting shortening experiments to model accretionary wedges at subduction margins under several basement configurations of the subducting plate. Slope failures periodically occur when thrust faults reach the top surface of the models. These failures are triggered by steepening of slopes related to the displacement along the underlying thrusts. Internal stress field and physical property of materials may have little impact on the pattern and geometry of failures. Experiments with a topographic relief (e.g., horst) in the basement produce irregular distribution in time of thrusting. Long-lived thrusts, generally initiate at the foot of topographic highs, tend to form longer slopes with thick piles of failed sediments in the footwall. These suggest that anomalous amount of failed sediments in accretionary wedge regions can be used to assume topographic relief in the basement that affected the geometry of detachment. When subducted, such detachment geometries may not be easy to recognize with geophysical technique.