## 2 Understanding the Key Extracellular Matrix Proteins
### ECM Synthesis
MMPs are categorised into six groups including collagenases and gelatinases, based on their structure and enzymatic substrates [27]. MMPs are secreted as inactive pro-enzymes, pro- MMPs, and are activated by proteolytic degradation of the amino terminals exposing the Zinc ion (Zn\({}^{2+}\)) binding pocket of the catalytic domain [28]. Activated MMPs cleave at specific sites, and therefore, breakdown the ECM scaffold or they can modify bioactive molecules that exist within the ECM proteins [27]. The activity of MMPs is counterbalanced by TIMPs that block the activation pathway and hence inhibit MMPs binding to ECM substrates. There are four members in the TIMPs family, TIMP-4. The ratio of MMP to TIMP determines the overall ECM degradation. A disease example that illustrates the importance of ECM homeostasis is cardiomyopathy, where increased levels of MMP-1 reduce collagen content and thus reduced cardiac contractility [29]. The increased overexpression of MMP-1 is associated with an increased ratio of MMP-1/TIPM-1 in dilated cardiomyopathy [30]. In vessel wall development and remodelling, MMPs also have an inflammatory mediated function, similar to cytokines, as they are actively expressed in diseased tissue but absent or expressed at very low levels in healthy tissue [27]. In vascular tissues inflammatory cells, including macrophages and neutrophils, are important sources of MMPs [27]. Tissue injury or pathologic conditions can also lead to excessive production and accumulation of ECM proteins, \begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**ECM Component** & **Type** & **Function** & **Reference** \\ \hline
**Laminin** & Glycoprotein & Regulate vital ECM activities including cell adhesion, migration, differentiation and proliferation. & [PERSON] et al., 2009 [18] \\ \hline
**Fibronectin** & Glycoprotein & Interactions with cells to link the ECM to the intracellular cytoskeleton and signalling pathways & [PERSON] et al., 1998 [19] \\ \hline
**Tenascin** & Glycoprotein & Carries out adhesive and counter adhesive activities upon binding of the ECM proteins to cell surface receptors & [PERSON] et al., 2000 [20] \\ \hline
**Glycosaminoglycans** & Heterogenous polysaccharide & Heterogenous polysaccharide & Heterogenous providing they exhibit a positive charge on their surface. These interactions play essential roles in normal physiology and pathogenic processes. & [PERSON] et al., 2014, [PERSON] et al., 1998 [21; 22] \\ \hline
**Proteoglycan (PG)** & GAG covalently linked to a core protein & Retain water that hydrates that ECM generating a swelling pressure that aids the ECM to resist compressive forces. & [PERSON], 1993 [23] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Cont. ultimately leading to fibrosis [15]. Fibrosis is the body's natural response mechanism to injury whereby a scar is formed as part of the wound healing process. However, if the tissue properties within the scar region are not the same as the native surrounding tissue, it can lead to organ failure, such as liver cirrhosis [1] and heart failure [31]. The fibrotic response is driven by a variety of cell types, growth factors and cytokines and can be inhibited by signalling mediators such as interferon-\(\gamma\) (IFN-\(\gamma\)), an antagonist to TGF\(\beta\)[15].