Title:Physiological Properties, Functions, and Trends in the Matrix Metalloproteinase
Inhibitors in Inflammation-Mediated Human Diseases
Volume: 30
Issue: 18
Author(s): Il-Sup Kim, Woong-Suk Yang*Cheorl-Ho Kim*
Affiliation:
- Nodaji Co., Ltd., Pohang, Gyeongsangbuk-Do 37927, Republic of Korea
- Molecular and Cellular
Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Suwon, Gyunggi-Do
16419, Republic of Korea
- Samsung Advanced Institute of Health Science and Technology (SAIHST),
Sungkyunkwan University, Seoul 06351, Republic of Korea
Keywords:
Matrix metalloproteinases (MMP), MMP-9, MMP-mediated pathogenesis, inflammation, MMP inhibitors, ECM region.
Abstract:
Background: Matrix metalloproteinases (MMPs), also known as metalloproteinases, are
enzymes that degrade proteins and require the presence of active metal atoms. There are more than
20 types of MMPs, and they promote cell migration through the proteolytic degradation of the extracellular
basement. MMPs are upregulated in cancers and inflamed regions. MMPs have three
conservation regions: pro-MMP, catalysis, and hemopexin. Through these domains, MMPs cleave
matrixes and cell-cell barriers. Consequently, MMPs cleave the whole extracellular matrix (ECM).
In other words, they decompose most of the components related to the ECM, in their roles as key
enzymes in cellular and pathophysiological events in the body.
Introduction: Zn2+-containing endo-type peptidases directly degrade and remodel the ECM region
in the progression of various diseases. MMPs are frequently found in abnormal disease status of inflammatory
responses, periodontal lesion, inflammatory pulmonary lesion, arteriosclerotic smooth
muscles, arthritis, and tumor metastasis and invasion. They are also known to participate in aging
processes-such as wrinkle formation-by destroying collagen in the dermis. In particular, the onset
of diseases via the MMP-dependent inflammatory response is caused by the breakdown of proteins
in the ECM and the basement membranous region, which are the supporting structures of cells.
Methods: This review describes the developments in the research examining the general and selective
inhibitors for MMP associated with various human diseases over the past 20 years in terms of
structure remodeling, substrate-recognizing specificities, and pharmacological applicability.
Results: Among two similar types of MMPs, MMP-2 is known as gelatinase-A with a 72 kDa,
while MMP-9 is termed gelatinase-B with a 92 kDa. Both of these play a key role in this action.
Therefore, both enzymatic expression levels coincide during the onset and progression of diseases.
Endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) are highly specific for each
MMP inhibitor type. The intrinsic factors regulate various MMP types by inhibiting the onset of
various diseases mediated by MMP-dependent or independent inflammatory responses. The MMP-
9 and MMP-2 enzyme activity related to the prognosis of diseases associated with the inflammatory
response are selectively inhibited by TIMP1 and TIMP2, respectively. The major pathogenesis
of MMP-mediated diseases is related to the proliferation of inflammatory cells in various human
tissues, which indicates their potential to diagnose or treat these diseases. The discovery of a substance
that inhibits MMPs would be very important for preventing and treating various MMP-dependent
diseases.
Conclusion: Considerable research has examined MMP inhibitors, but most of these have been
synthetic compounds. Research using natural products as MMP inhibitors has only recently become
a subject of interest. This review intends to discuss recent research trends regarding the physiological
properties, functions, and therapeutic agents related to MMPs.
