Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Abstract

Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes that degrade various proteins in the extracellular matrix (ECM). MMPs may also regulate the activity of membrane receptors and post-receptor signaling mechanisms, and thereby affect cell function. The MMP family includes collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and other MMPs. Inactive proMMPs are cleaved by other MMPs or proteases into active MMPs, which interact with various protein substrates in ECM and cell surface. MMPs regulate important biological processes such as vascular remodeling and angiogenesis, and may be involved in the pathogenesis of cardiovascular disorders such as hypertension, atherosclerosis, and aneurysm. The role of MMPs is often assessed by measuring their mRNA expression, protein levels, and proteolytic activity using gel zymography. MMP inhibitors are also used to assess the role of MMPs in different biological processes and pathological conditions. MMP activity is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP balance could determine the net MMP activity, ECM turnover, and tissue remodeling. Also, several synthetic MMP inhibitors have been developed. Synthetic MMP inhibitors include a large number of zinc binding globulins (ZBGs), in addition to non-ZBGs and mechanism-based inhibitors. MMP inhibitors have been proposed as potential tools in the management of osteoarthritis, cancer, and cardiovascular disorders. However, most MMP inhibitors have broad-spectrum actions on multiple MMPs and could cause undesirable musculoskeletal side effects. Currently, doxycycline is the only MMP inhibitor approved by the Food and Drug Administration. New generation biological and synthetic MMP inhibitors may show greater MMP specificity and fewer side-effects, and could be useful in targeting specific MMPs, reducing unrestrained tissue remodeling, and the management of MMP-related pathological disorders.

Urinary TIMP‐2 and MMP‐2 are significantly associated with poor bladder compliance in adult patients with spina bifida

“…Recently, early blockade of matrix metalloproteinase with GM6001, a broad‐spectrum matrix metalloproteinase inhibitor, was shown to increase bladder compliance in the long run in spinal cord injured dogs . Numerous matrix metalloproteinase inhibitors have been investigated in recent years in various conditions making the exploring of this possible therapeutic pathway feasible and relevant . Several other therapeutic interventions aiming to reduce the production of extracellular matrix have been examined over the past few years, ranging from vitamin‐D or endostatin to antifibrotic hormone relaxin .…”

“…23 Numerous matrix metalloproteinase inhibitors have been investigated in recent years in various conditions making the exploring of this possible therapeutic pathway feasible and relevant. 24 Several other therapeutic interventions aiming to reduce the production of extracellular matrix have been examined over the past few years, ranging from vitamin-D or endostatin to antifibrotic hormone relaxin. 22 All these investigational therapies might be interesting to investigate in patients with spina bifida having poorly compliant bladder.…”

Metalloproteases and Inhibitors Expression in Myocardium Under Ischemic Conditions After Allogenic Biomaterial Introduction

“…Установленная корреляция между изменением баланса протеолитической активности ММР-9/ ТIМР-2 и накоплением внеклеточного матрикса согласуется с данными других исследователей [14].…”

Matrix-targeted Nanoparticles for MMP13 RNA Interference Blocks Post-Traumatic Osteoarthritis

“…homeostasis (18)(19)(20). Production of selective small molecule inhibitors is complicated by shared 10 domains of the collagenases and the homology of the catalytic site (21). One tested MMP13 "specific" 11 inhibitor PF152 reduced lesion severity in a canine PTOA model (22) but unfortunately caused 12 nephrotoxicity believed to be caused by off-target effects on the human organic anion transporter 3 13 (which can be circumvented with our proposed RNAi due to sequence specificity and not structural 14 specificity) (23).…”