Biology Reference
In-Depth Information
with both triple-helical and globular motifs. After being laid down during embry-
onic development or postnatal tissue remodeling, collagen bundles, networks, and
sheaths are strengthened by extensive intra- and intermolecular crosslinking cata-
lyzed by the enzyme lysyl oxidase and by nonenzymatically crosslinks formed
between glycated lysine and hydroxylysine residues (Linsenmayer
1991
; Reiser
et al.
1992
; van der Rest and Garrone
1991
). In this way, the collagens form
covalently linked structures that are multiple orders of magnitudes larger than the
individual cells that laid them down (Birk and Br
uckner
2011
).
The unique supramolecular organization of the collagens makes them remark-
ably resistant to proteolytic degradation by the complement of about 300 proteo-
lytic enzymes that reside within the extracellular and pericellular environments, and
the half-life of collagen in some adult tissues is measured in years or even decades.
However, embryonic development, postnatal growth, tissue remodeling, and tissue
repair all require the targeted remodeling of existing interstitial and basement
membrane collagen to allow for organ growth, cell migration, and translation of
contextual clues that are embedded within the extracellular matrix. Furthermore, a
number of degenerative and proliferative diseases, such as osteoarthritis, osteopo-
rosis, rheumatoid arthritis, and neoplasia, are characterized by the extensive and
detrimental turnover of collagen-rich tissues, which has spurred considerable inter-
est in understanding the mechanics of collagen degradation and exploring mole-
cules involved in collagen degradation as therapeutic targets. Studies spanning a
wide range of scientific disciplines have amalgamated over the last 40 years to
delineate these collagen turnover pathways and identify specific proteolytic
enzymes and cellular receptors that mediate both the normal (physiological) and
the abnormal (pathological) degradation of collagen. One of the identified pathways
involves a group of secreted or membrane-associated matrix metalloproteinases,
the collagenases, and takes place within the pericellular/extracellular environment.
A second pathway is mediated by the cysteine cathepsins and takes place in the
acidic microenvironment that is created at the osteoclast-osteoid interface specifi-
cally during bone turnover (Gelb et al.
1996
; Saftig et al.
1998
). A third pathway is
intracellular and involves the binding of collagen fibrils to endocytic cell surface
receptors, followed by the cellular uptake and proteolytic degradation of the inter-
nalized collagen in the lysosomal compartment (Everts et al.
1996
). This chapter
will briefly describe each of these collagen degradation pathways, and it will
summarize the limited knowledge as well as current speculations as to how these
systems functionally cooperate to facilitate the stepwise and complete turnover of
this abundant extracellular matrix component.
€
3.2 Extracellular Pathways for Collagen Degradation
3.2.1 Matrix Metalloproteinases
The matrix metalloproteinases (MMPs) constitute a family of 25 structurally related
secreted and membrane-bound metalloenzymes (Parks and Mecham
1998
). All MMPs
