Matrix Metalloproteinases in the Interstitial Space

Matrix metalloproteinases (MMPs) are a family of proteases that function in the extravascular space (see Appendix). The MMP system is an important component of the interstitial system of degradation of the extracellular matrix (ECM) during normal tissue remodeling or during metastatic disease. ^{1 – 5} MMPs have broad specificity, with many having similar sites of cleavage, ⁶ and can be considered both digestive proteases and regulatory proteases as well as being evaluated as biomarkers. It can be argued that, for some MMPs, their most significant role is in the degradation of collagen, as demonstrated by the roles of MMP-1 and MMP-3 as effectors of TNF-a action on the skin. ⁷ Here, MMP-3 can be considered a regulatory protease for its role in stimulating MMP-1 activity ⁸ (Table 7.1). It should be noted that MMP-1 digestion of collagen enables the subsequent digestion of collagen by MMP-9. ⁹ The ability of other proteases such as plasmin and thrombin to activate MMPs results in a carefully regulated environment for phenomena such as tumor progress, tissue remodeling, and wound healing. ¹⁰ Exposure to cigarette smoke not only induces the production of MMP-1 but also promotes the activation of pro-MMP-1. ¹¹ This observation is noted to indicate the complexity of factors that govern MMP functional expression, including redox systems.^12–14 The suggestion that oxidants in cigarette smoke may be responsible for the activation of pro-MMP-1 has to be considered speculation in the absence of other data. Table 7.1 Activation of Pro-MMPs by Proteases

MMP a	Furin b	Trp a	Plm a	IIa a	CHT a	FXa a	MMP-3 a	MMP-10 a	MMP-13 a	MMP-14 a	PKA a	Tryptase	Tgn-2 a
1		+	+				+	+					+
2	+	+	+	+		+				+
3		+	+		+						+	+
7		+	+				+
8							+				+		+
9		+	+		+		+		+		+
10		+	+		+
11	+
12		+	+
13		+	+							+			+
14	+
15	+
16	+
17	+
18
19		+
20										+
21
22
23
24
25
26
27
28

Note: As reported in the peer-reviewed literature, only positive results are reported. a

Matrix metalloproteinase (MMP).

b

Furin is one of several proprotein convertases, which are a family of proteolytic enzymes involved in the processing of proteins either for secretion or expression on the cell surface. In most cases, a specific proprotein convertase is not identified. (From Seidah, N.G., et al., J. Biol. Chem. 288, 21473–21481, 2013.)