Metalloproteases in Achilles Tendinopathy

Disorganized healing is constant in chronic tendinopathy. Normal tendon is mostly composed of Type I collagen, while tendinopathic tendons have a greater proportion of Type III collagen, which is associated with tendon rupture.30 Matrix metalloproteases (MMPs) are involved in remodeling of the extracellular matrix (ECM) of tendons, being either up- or down-regulated in tendinopathy. A balance between MMPs and tissue inhibitors of metalloproteases (TIMPs) is probably necessary to maintain tendon homeostasis. The mechanism of activation of MMPs is poorly understood, and their precise role in tendinopathy is still unclear.

Degradation of collagen and other ECM compounds is initiated by matrix metalloproteases (MMPs).31 These are zinc and calcium-dependent endopeptidases secreted from cells in proenzyme form.32 MMPs are the major enzymes involved in remodeling of ECM because of their efficacy at neutral pH and their broad proteolytic capability against the ECM.33

The MMP family comprises 23 members,33 subdivided into four main classes: collagenases, gelatinases, stromelysins, and membrane-type MMPs.34 MMPs are involved in many other physiological remodeling processes, including wound healing, menstruation, uterine involution, bone growth and development, and angiogenesis.35-37 They also play a role in pathological processes such as tumor invasion and metastasis,38-42 multiple sclerosis,43 periodontal disease,44,45 hyperten-sion,46 and arthritis.47-54

The activity of MMPs is inhibited by tissue inhibitors of metalloproteases (TIMPs).55,56 The balance between the activities of MMPs and TIMPs regulates tendon remodeling. An imbalance in MMPs and TIMPs is associated with collagen dis-turbances.57 Cytokines such as interleukin-1 (IL-

1) and tumor necrosis factor a (TNFa) enhance the production of MMPs,58-60 whereas transforming growth factor P (TGFP) and IL-6 enhance the production of TIMP-1.61,62

MMPs can be up- or down-regulated, locally and systemically, in tendinopathy and complete tendon tears. A balance exists between expression of MMPs and TIMPs to maintain tendon homeo-stasis. More research is required to determine the mechanism of action and regulation of MMPs in tendinopathy to promote the development of specific therapeutic strategies in these patients.63

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