**4.2. Inhibition of matrix metalloproteinases by tissue inhibitors of metalloproteinases**

of myofibres, leading to uncontrolled influx and efflux of ions and subsequent myopathy [31, 32]. Because of their ability to degrade ECM components, MMPs are considered to be important components in many biological and pathological processes [30–32]. They have regulatory roles in muscle growth and development and are also important in repair processes after traumatic injury or disuse myopathy [30,31]. MMPs are mainly produced from endotendon fibroblasts and intramuscular matrix fibroblasts [30,31], although some level of expression has been found to occur also in satellite cells [33]. MMPs are secreted or released in latent form and become activated in pericellular environments [23,34]. The activities of MMPs are also under the control of enzyme tissue inhibitors of matrix metalloproteinases (TIMPs). Disturbances in the ratio of specific MMPs and their inhibitors may be manifested by physiological dysfunction,

Up until now, 24 different vertebrate MMPs have been identified, of which 23 have been found in humans. MMPs are usually divided according to their main substrate into collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others, although many of

MMP-1, MMP-8, MMP-13 and MMP-18 are collagenases, which have the ability to cleave the native helical structure of collagens I, II and III. Cleavage products are then susceptible to the

Gelatinases MMP-2 and MMP-9 degrade denatured collagen, gelatin, native type IV, V and VII collagens as well as other ECM components [36]. One of the most important MMPs associated with the function and dysfunction of the skeletal muscle appears to be MMP-2, also known as gelatinase A, or 72-kDa type IV collagenase. MMP-2, by regulating the integrity and composition of the ECM in skeletal muscle, plays essential role in myofibre proliferation and differentiation, the fibre healing after injury, and maintenance of the surrounding connective tissue [38]. MMP-2 also digests fibrillar type I and II collagens. MMP-2 and –9 are known to be overexpressed and present in higher amounts in patients with inflammatory myopathies, which may increase ECM degradation and thus facilitate lymphocyte adhesion [32,38,39].

MMP-3 and MMP-10, or stromelysin-1 and –2, both digest ECM components and activate proMMP-1. The third stromelysin, MMP-11, differs from other stromelysins by its sequence

Matrilysins- MMP-7 and MMP-26 are the smallest MMPs. MMP-7 can also process cell surface

Six membrane-type MMPs (MT-MMPs) have been characterized. Except the MT4-MMP, they all are all capable to activate proMMP-2 [36,40]. For their pericellular fibrinolytic activity, MT-

Six MMPs – MMP-12, MMP-19, MMP-20, MMP-22, MMP-23, MMP-28 are currently classi‐

resulting in clinical disorders [31,35].

action of other MMPs [36,37].

and substrate specificity [36].

MMPs have an important role in angiogenesis [36,40].

fied into the group of "other MMPs" [34,36].

molecules [36].

them have wide and overlapping substrate specificity [36].

52 Composition and Function of the Extracellular Matrix in the Human Body

MMPs and tissue inhibitors of metalloproteinases (TIMPs) have an important role in the adaptive changes in the muscle in response to local developmental, physiological, surgical, and pathological conditions [31,39]. TIMPs are the major cellular inhibitors of the MMP subfamily, exhibiting varying efficacy against different members, as well as different tissue expression patterns and modes of regulation [36,41]. Four mammalian TIMPs have been characterized and considered to regulate MMP activity during tissue remodelling [41,42]. All four TIMPs (TIMP-1, -2, -3 and –4) can inhibit all MMPs, except TIMP-1, which is a poor inhibitor of MMP-19 and most of the MT-MMPs [41,42]. Although TIMP-2 inhibits MMP-2 in high concentrations, it has an important role in activating proMMP-2 in a complex with MT1- MMP, which demonstrates an integrated response of MMPs and TIMPs [43]. In skeletal muscle, TIMP-1, TIMP-2 and TIMP-3 are expressed [33,39]. TIMP-4 appears to be cardiac-specific and has not been detected in the skeletal muscle [37].

The increased MMP activity and thus the enhanced degradation of collagen often parallels the stimulated activation of collagen synthesis. TIMPs are often activated together with MMPs in response to physical activity, indicating a simultaneous stimulation and the inhibition of degradation [44,45]. MMP activity precedes TIMP activity and thus TIMP serves as the regulator of degradation termination to ensure a limited amount of degradation [39,43].

In addition to MMP-binding activities, TIMPs have many important biological functions. TIMPs can promote or inhibit cell growth, depending on the type of the cell and the inductor [36,41].
