Chondromodulin-I and tenomodulin: the negative control of angiogenesis in connective tissue.
The negative regulation of angiogenesis may provide a promising therapeutic target for a number of lifestyle-related diseases, as the switch to an angiogenic phenotype in many tissues represents a critical step during the progression of such disorders. Cartilage is avascular and shows resistance to vascular invasion from the surrounding well-vascularized mesenchyme. Using guanidine extracts of fetal bovine cartilage, we have identified and purified chondromodulin-I (ChM-I) as an angiogenesis inhibitor. The cDNA sequence of this factor has revealed that the ChM-I precursor protein is a type II transmembrane glycoprotein (334 amino acids) and that mature ChM-I is encoded in the C-terminal region of the precursor. After cleavage of the ChM-I precursor at its processing site, mature ChM-I (120 amino acids) is secreted from chondrocytes into the extracellular matrix. Following on from the identification of ChM-I as an angiogenesis inhibitor in cartilage, we have also cloned both mouse and human tenomodulin (TeM), which share significant homology with ChM-I at their C-termini. Moreover, exogenous expression experiments in COS cells suggests that TeM is a type II transmembrane glycoprotein (317 amino acids). When overexpressed in HUVECs, the C-terminal domain (116 amino acids) of the TeM protein shows both anti-angiogenic and anti-tumorigenic activities at equivalent levels to mature ChM-I. In our present review, we discuss the structure, biological activities and localization of these anti-angiogenic molecules.
Shukunami
Chisa
C
Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Shogoin-Kawahara-cho, Kyoto, Japan.
Hiraki
Yuji
Y
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003238:Connective Tissue / Q000098:blood supply / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D008648:Mesoderm / Q000187:drug effects; D008969:Molecular Sequence Data; D015394:Molecular Structure
D020533:Angiogenesis Inhibitors; C489408:Cnmd protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C422444:TNMD protein, human; C486026:Tnmd protein, mouse; C068675:CNMD protein, human