## 2 Understanding the Key Extracellular Matrix Proteins  
### ECM Synthesis  
The ECM is a complex, heterogenous collection of different molecules. Over the last two decades intensive research into ECM proteins has generated new insights into ECM composition and function in both healthy and diseased tissues [13]. The exact number of ECM proteins remains an open question and is an active area of research; however, it is estimated that there are between 300-400 ECM genes, with a third of them still to be identified [14]. ECM components are commonly categorised into two groups: **fibre-forming** and **non-fibre-forming** molecules [3]. The typical fibre-forming molecules include specific classes of collagen and elastin and the non-fibre-forming molecules include proteoglycans and glycoproteins (Figure 1). It is paramount to have a tight regulation between the molecules signalling ECM synthesis and degradation as this is essential for maintaining the structural integrity and thereby the tissue and organ functions. ECM proteins are located within these two basic compartments (Figure 2): (i) interstitial connective tissue, that surrounds cells providing a structural matrix for the tissues and (ii) specialised basement membrane that separates the epithelium and the stroma and is involved in the matrix-cell interactions [15]. These two compartments of the ECM are characterised by different components with the interstitial matrix comprised of molecules, including type I collagen, fibronectin, proteoglycans (PGs), glycosaminoglycans (GAGs), tenascin C and elastin, whereas the basement membrane is comprised of type IV collagen, laminins and nidogen. Dysregulated ECM composition either because of excessive ECM production and/or increased degradation is observed in various diseases including cardiac, lung, liver, cancer, deep vein thrombosis and osteoarthritis [15]. A summary of these common ECM components with respective functions are provided in Table 1.  
Figure 1: Components of the extracellular matrix (ECM). \begin{table}
\begin{tabular}{c c c c} \hline
**ECM Component** & **Type** & **Function** & **Reference** \\ \hline \multirow{3}{*}{**Collagen**} & \multirow{3}{*}{Fibrous protein} & Main structural component of the ECM that provides strength, regulates adhesion and supports chemotaxis and migration. [PERSON] et al., 2010 [16] \\ \cline{3-4}  & & Main structural component of the ECM that provides elasticity and reliance to tissues undergoing stretching. [PERSON], 1978 [17] \\ \hline \end{tabular}
\end{table} 
Table 1: Summary of common ECM components with their respective functions. The components have been categorised into structural ECM proteins (green); adhesion proteins (orange); glycosaminoglycans and proteoglycans (blue). Figure 2: The two basic compartments of the extracellular matrix. Understanding the underlying biosynthesis and assembly of the ECM proteins is essential for various disciplines, including the development of molecular imaging probes and drugs, tissue engineering and regenerative medicine. The turnover of ECM proteins is regulated by various cell types, including fibroblasts, mast cells and macrophages, growth factors such as the transforming growth factor-\(\beta\)s (TGF-\(\beta\)s) and enzymes including matrix metalloproteinases (MMPs). In the late 1980s, it was first shown that TGF-\(\beta\) has the ability to control synthesis of ECM proteins [24; 25]. Subsequently, in 1986, [PERSON] et al. demonstrated that injecting TGF-\(\beta\) in new-born mice activated the rough endoplasmic reticulum (RER) of fibroblasts stimulating the production of extracellular collagen fibres [24; 25]. The pro-fibrotic effect of TGF-\(\beta\) is complemented with its ability to inhibit the proteolytic degradation of ECM proteins [25] by increasing the production of tissue inhibitors of matrix metalloproteinases (TIMPs) [26]. MMPs are a class of enzymes that have been studied since 1962 with 23 human MMPs identified to date [15].