|Lysyl oxidases: Cloning and characterization of the fourth and the fifth human lysyl oxidase isoenzymes, and the consequences of a targeted inactivation of the first described lysyl oxidase isoenzyme in mice|
To this date, five human lysyl oxidase isoenzymes have been characterized (Hämäläinen et al. 1991, Mariani et al. 1992, Kenyon et al. 1993, Saito et al. 1997, Jourdan-Le Saux et al. 1999, Asuncion et al. 2001, Huang et al. 2001, Jourdan-Le Saux et al. 2001, papers I and II in present study). All these isoenzymes are likely to be able to use both elastin and collagens as their substrates, as has so far been shown for LOX (Kagan 1986), LOXL (Borel et al. 2001), and LOXL4 (Ito et al. 2001). The primary structures of the LOX and LOXL polypeptides differ dramatically from those of the most recently characterized isoenzymes LOXL2, LOXL3, and LOXL4. The differences in the structural properties of these isoenzymes may indicate differences in their functions or their location in the extracellular matrix. This would be plausible since LOX is known to have a very broad substrate specifity (see Smith-Mungo & Kagan 1998 for review) and may have unidentified intracellular (Wakasaki & Ooshima 1990b) or intranuclear substrates (Li et al. 1997). The use of monoclonal and polyclonal antibodies prepared against the recently identified isoenzymes should provide more information about their tissue distribution, their expression in various cell types, and even their location within the cell. Further purification of the new isoenzymes would provide a proper tool for their extensive functional and biochemical characterization.
Since the lack of Lox activity leads to highly fragmented elastin fibers in the aorta, it can be assumed that abnormalities in elastic fibers may be found also in other tissues. The manifestations in lathyrism, Menkes disease, and OHS include several defects associated with abnormal elastic fibers, but also defects in collagens in various tissues. Although no major abnormalities were observed in collagen fibers of Lox-/- embryos by electron microscopy, further immunological and biochemical analyses of collagens are needed. Therefore, further detailed and extensive analyses of Lox-/- embryos may provide essential information about possible specific roles of Lox in various cell and tissue types, and in certain developmental stages of the growing embryo.
The heterozygous adult Lox+/- mice may turn out to be valuable animal models for research on certain cardiovascular diseases. By using the Cre/loxP-method, a conditional or tissue-specific knockout mouse model could be produced in the future, thus giving the opporturnity to analyze the consequences of the lack of Lox activity in adult mice.
|Lack of Lox activity leads to a severe cardiovascular dysfunction and perinatal death in mice (III)||References|