Biology Reference
In-Depth Information
MAGP, other microfibril components, and components of the basement membrane.
We will briefly discuss the assembly of the amorphous elastic fiber and its interac-
tions with microfibrils.
9.2.6.1 Lysyl Oxidases
Lysyl oxidases are a class of copper-requiring enzymes that help to cross-link both
collagen and elastin. There are five members of this group. In addition to LOX there
are four lysyl oxidase-like proteins (LOXL1-4) that contain a conserved amino
oxidase domain. There appear to be two subfamilies based on homology: (1) LOX
and LOXL1 and (2) LOXL2,
4 (Lucero and Kagan
2006
). LOX and
LOXL1 are the only two that have been shown to cross-link elastin (Borel et al.
2001
). LOX and LOXL1 enzymes are essential in the assembly phase of tropoe-
lastin/elastin and with linking to the microfibrils (Hayashi et al.
2004
; Kielty
2006
).
They are released as a proform and require processing by bone specific proteases
such as bone morphogenic protein-1 (BMP-1) (Borel et al.
2001
).
Elastin cross-linking occurs at lysine residues that are modified to form bi-, tri-,
and tetrafunctional cross-links (Wagenseil and Mecham
2007
). Desmosine is a
crosslink of three allysyl side chains with one unaltered lysyl side chain from the
same or neighboring polypeptide, and isodesmosine is a lysine derivative whereby
four lysines are formed into a pyridinium ring. Both of these are unique to elastin
and due to lysyl oxidase cross-linking. LOX can cross link tropoelastin directly
whereas LOXL1 can interact with fibulin-5 also (Liu et al.
2004
). Interestingly, the
prodomain of these enzymes directs them to elastic fibers in vitro and may account
for some of the differences between the two enzymes (Thomassin et al.
2005
).
Lox
/
mice die at the end of gestation or quickly after birth with aortic aneurysms
and diaphragm collapse. Furthermore, there is an approximate 60% reduction in
desmosine cross-links in the aorta and lungs. These mice also show impaired
collagen development (Maki et al.
2002
; Hornstra et al.
2003
; Maki et al.
2005
).
LOXL1
/
mice have a less severe phenotype. They develop pelvic prolapse, loose
skin, congenital emphysema, and vascular deformities, but have a normal life span
(Liu et al.
2004
).
3, and
9.2.6.2 Development
Most elastin is formed during embryogenesis and early in life. Both carbon and
racemization dating in human lungs show that fibers dated to the patient's age
without evidence of significant turnover (Shapiro et al.
1991
). Analysis of elastin
protein in mice shows that most of the elastic fiber proteins are expressed during the
second half of embryogenesis and continue through the early postnatal period
(approximately P7-14) (Kelleher et al.
2004
). In the lungs, however, there are
two peaks of elastogenesis in mice occurring at day E18 and between days P10-14.
The former peak is felt to coincide with vascular development in the lungs and the
