Matrix Metalloproteinases and Their Inhibitors in Turnover and Degradation of Extracellular Matrix - Extracellular Matrix Degradation - page 5

(Shapiro et al. 1991 ). Although turnover does involve degradation (it is the balance
between synthesis and degradation), we will use the term degradation to indicate
untimely or excessive matrix destruction as seen in disease, typically chronic
inflammatory conditions such as arthropathies, emphysema, and vascular disease.
Remodeling will be used to indicate the breakdown of matrix in tissues undergoing
normal architectural changes, such as clearance of tissue in the formation of digits,
involution of the postpartum uterine, and scar resorption in a healed wound bed.
1.2.2 Gain-of-Function Processing
The three terms discussed above - turnover, degradation, and remodeling - all
indicate catabolism of ECM, in essence, a loss-of-function process. However,
proteolysis does not need to be defined as simply destruction. Another term -
processing - refers to the proteolytic posttranslational modification of (typically)
latent proteins. Proteolysis is a common mechanism used to control the activity
of numerous, diverse proteins that function in the extracellular space (e.g., the
coagulation and complement cascades, latent cytokines, prohormones, neuropep-
tides, digestive enzymes, and processing of ECM precursors). Thus, proteolysis -
either inside cells or out - can be anabolic mediating gain-of-function processing.
As we have argued elsewhere (Gill et al. 2010b ; Parks et al. 2004 ), we propose that
the processing of latent proteins is the predominant function of MMPs.
A related term is cleavage , which indicates proteolysis at a single site (or more)
generating two (or more) discreet protein fragments. Cleavage can involve either
loss-of-function proteolysis, such as the single-site splitting of fibrillar collagen by
MMP1, preparing the substrate for more thorough proteolysis by other enzymes, or
gain-of-function proteolysis, such as removal of propeptide from a latent growth
factor or shedding of bioactive ectodomains.
1.3 Do MMPs Function in Proteolysis of the Extracellular
Matrix?
The short answer to this question is yes, some do. However, it has become clear that
ECM turnover or degradation is neither the sole nor the predominant function of
these proteinases. So how did the assumption, and one that has reached dogmatic
status, arise that MMPs are the main matrix degrading enzymes in our body? The
answer lies in the history of the MMP field. The first MMP was discovered by Gross
and Lapiere ( 1962 ). At the time, the only known collagenolytic enzymes were
cysteine proteinases, such as those produced by osteoclasts for turnover of organic
bone matrix. However, cysteine proteinases function at an acidic pH (see Chap. 2),
yet it was known that fibrillar collagen also are turned over in tissue where the