The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases

Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM. The degradation of the ECM is of great importance, since it is related to embryonic development and angiogenesis. It is also involved in cell repair and the remodeling of tissues. When the expression of MMPs is altered, it can generate the abnormal degradation of the ECM. This is the initial cause of the development of chronic degenerative diseases and vascular complications generated by diabetes. In addition, this process has an association with neurodegeneration and cancer progression. Within the ECM, the tissue inhibitors of MMPs (TIMPs) inhibit the proteolytic activity of MMPs. TIMPs are important regulators of ECM turnover, tissue remodeling, and cellular behavior. Therefore, TIMPs (similar to MMPs) modulate angiogenesis, cell proliferation, and apoptosis. An interruption in the balance between MMPs and TIMPs has been implicated in the pathophysiology and progression of several diseases. This review focuses on the participation of both MMPs (e.g., MMP-2 and MMP-9) and TIMPs (e.g., TIMP-1 and TIMP-3) in physiological processes and on how their abnormal regulation is associated with human diseases. The inclusion of current strategies and mechanisms of MMP inhibition in the development of new therapies targeting MMPs was also considered.

MMPs play an important role in tissue remodeling during various physiological processes, such as embryogenesis, morphogenesis, angiogenesis, and wound repair. During normal biological processes, such as pregnancy and wound healing, alterations in MMP expression and activity occur [ 1 ]. MMPs and TIMPs are of great importance in the morphogenesis of fetal organs and subsequent events, having roles such as increasing the activity of cardiac morphogenesis [ 1 ] and lung differentiation as well as events necessary for the culmination of pregnancy and childbirth ( Table 2 ) [ 2 ]. An example of the dynamic participation between MMPs and TIMPs occurs during lung differentiation and specialization, which occurs as a multistep process starting with branching morphogenesis (7–16 weeks of gestation (WG)), angiogenesis (16–24 WG), and alveolar generation (36 WG to 3 years old) [ 11 ]. Throughout morphogenesis, MMP-1, MMP-9, TIMP-1, TIMP-2, and TIMP-3 are detected in the fetal epithelium, while MMP-1, MMP-2, TIMP-2, and TIMP-3 are only expressed in the pulmonary vascular endothelium and media [ 11 , 22 ]. Afterwards, the canalicular stage is peculiar with regard to its angiogenesis and the linking of bronchiolar structures with their capillary interface. The last phase, the alveolarization stage, is characterized by alveolar development and maturation of the capillary network. This process requires MMP-14 and the coordination of extracellular matrix remodeling with epithelial morphogenesis and capillary growth [ 11 ]. After 20 WG, the main events that occur are substantial growth and weight gain. A considerable amount of subcutaneous fat appears with the formation of adipocytes from a precursor that involves two classifications: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is present in adults, while BAT is predominantly responsible for shivering thermogenesis in postnatal babies. [ 23 ]. Both of them require key transcription factors that are necessary to promote the differentiation of preadipocytes into mature adipocytes. The increased secretion of both MMP-2 and MMP-9 [ 24 ] was demonstrated through Western blot analysis and gelatin zymography. The results showed greater expression of MMP-2, MMP-9, and TIMP-2 by adipocytes. The amount of active MMP-2 increased as adipocytes differentiated [ 15 , 25 ]. On the other hand, the overexpression of TIMP-1 has been shown to result in enhanced involutional adipogenesis [ 16 ]. In addition, MMP-3 acts to slow down the adipogenic process [ 26 ]. MMP-11 plays a role in whole body metabolism and energy homeostasis, and it is a potent negative regulator of adipogenesis [ 27 , 28 ]. Bone develops in two different ways: mesenchymal cells can directly differentiate into bone by the process of intramembranous ossification (craniofacial skeleton) or it can differentiate into cartilage (endochondral ossification) and gradually turn into bone [ 17 ], with the latter being a process that occurs from the embryonic stage through to adulthood. One of the main MMPs implicated in endochondral ossification is MMP-13, which is derived from chondrocytes, synovial cells, and osteoblasts, and is considered the most important collagenase for the degradation of cartilage. It is induced by hypertrophic cartilage, and it plays a role in the degradation of type II collagen [ 19 ]. There are some secondary MMPs that also play important roles in this process, including MMP-2, MMP-9, MMP-14, and MMP-16. All of these are regulated at several levels, including gene expression, spatial localization, zymogen activation, and inhibition by naturally occurring inhibitors (TIMP-1–4), which are also expressed during endochondral ossification and osteocytic differentiation during bone matrix mineralization [ 19 ]. These kinds of regulatory events are described in the following sections. Normal Expression of MMPs and TIMPs in Adult Tissues Metalloproteinases and TIMPs are normally expressed in various tissues. However, it has been described that during the development of different human diseases, metalloproteinases 1, 2, 3, 7, 8, 9, 13, and 14 are overexpressed in specific tissues. These tissues include the kidneys, liver, colon, placenta, intestines, stomach, bladder, pancreas, ovary, uterus, and bone marrow, among others. TIMPs have variable expression in specific tissues such as the breast, brain, lungs, liver, kidneys, colon, skin, ovaries, and heart. In these tissues, TIMP-1 is overexpressed, TIMP-3 is underexpressed, and TIMP-2 and TIMP-4 can be either underexpressed or overexpressed ( Table 3 and Tables S1–S3 ).

The roles of MMPs and TIMPs in the maintenance of health and disease have gained interest. To understand how the regulation of these molecules plays a role in pathological conditions and how these molecules intervene in the secretion of growth factors, reactive oxygen species (ROS) and cytokines could be used to help to identify tools for better management of disease. Abnormal regulation of MMPs and TIMPs has a relevant role in pathological conditions, including inflammation, tissue destruction, fibrosis, abnormal angiogenesis, weakening of the matrix, microglial activation, autoimmune diseases, and carcinogenesis [ 86 ]. These compounds are involved in processes that include adhesion, cell proliferation, and migration and/or apoptosis by causing the cutting of bioactive molecules that modulate these processes [ 83 ]. The behaviors of MMPs and TIMPs in different sets of chronic diseases are described below. 4.1. MMPs and TIMPs in Diabetes Mellitus Globally, the number of people with diabetes mellitus (DM) has increased in the past three decades, and DM is within the top ten causes of death [ 87 ]. The prevalence of DM varies among different populations with a greater incidence of DM in individuals with a higher native American admixture [ 88 ]. Type 2 DM (T2DM) has a strong genetic component—if both parents have T2DM, the risk of an individual developing T2DM increases by 40%. The disease is polygenic and multifactorial [ 89 ]. Insulin resistance, impaired insulin secretion, abnormal fat metabolism, excessive hepatic glucose production, and systemic low-grade chronic inflammation characterize T2DM. As insulin resistance and compensatory hyperinsulinemia progress, it is more difficult to sustain the hyperinsulinemic state [ 90 ]. DM is a disease that is considered a risk factor for cardiovascular disease (CVD) [ 91 ]. Hyperglycemia is one of the main feature of the disease, and it generates damage to the vascular system, nerves, eyes, kidneys, and heart [ 92 ]. MMPs and TIMPs are often regulated as a means to control excess MMP activity in DM. In patients with DM, constant hyperglycemia generates oxidative stress (OS). The synthesis of MMP-9 is induced by sustained hyperglycemia. This was demonstrated at the protein level, as the expression and activity of MMP-9 increased as a consequence of the oxidative stress generated in vascular endothelial cells [ 93 ]. TIMP-1 can mitigate the death of β cells in type 1 DM, because it enhances the replication of pancreatic islet β cells. Thus, the TIMP-1 gene may be a potential target in the prevention, or even reverseal, of type 1 DM [ 94 ]. However, TIMP-1 has also been associated with low-grade chronic inflammation in the adipose tissue of patients with T2DM [ 95 ]. Individuals with T2DM in combination with arterial hypertension exhibit maximum TIMP-1 levels and TIMP-1:MMP-2 and TIMP-1:MMP-9 ratios, as well as enhanced secretion of tumor necrosis factor alpha (TNF-α), interleukin-16 (IL-6), and IL-17 [ 96 ]. TIMP-3 has also been implicated in the pathogenesis of DM and vascular inflammation [ 69 ]. TIMP-3 is unique among TIMPs, because it retains its ability to inhibit shedding enzymes, such as ADAM17, which are involved in inflammatory processes. In atherosclerotic plaques from subjects with T2DM, the deregulation of ADAM17 and MMP-9 activities is related to the inadequate expression of TIMP-3 via SirT1 [ 97 ]. There is increasing evidence of the roles of MMP-2, MMP-9, MMP-11, MMP-13, and TIMP-4 in DM and metabolic disorders. In vivo studies have shown that the inhibition of MMP-13 may be beneficial for the treatment of human diabetic neuropathy [ 98 , 99 ], whereas MMP-11 overexpression is protective against T2DM [ 27 ]. The concentrations and activity of MMP-2 and MMP-9 are increased in the urine of patients with T1DM and T2DM, especially in patients with albuminuria and established renal injury [ 100 ]. MMP-2 is strongly induced in the adipose tissue of obese patients [ 101 ] and underlies the pathogenesis of diabetic cardiomyopathy by increasing the extracellular collagen content [ 102 ]. MMP-9 mediates diabetes-induced retinal neuropathy and vasculopathy [ 103 ] and is associated with the severity of diabetic retinopathy [ 104 ]. The absence of TIMP-4 ameliorates high-fat diet induced obesity due to defective lipid absorption in vivo [ 105 ]. Therefore, MMP-2, MMP-9, MMP-11, MMP-13, and TIMP-4 could be important biomarkers to evaluate in diabetes and associated disorders. The ECM of the colon mucosa of patients with DM presents high levels of fibrillar collagen (types I and III) and fibronectin with an imbalance between the activities of MMPs and TIMPs and deregulation of the transforming growth factor beta 1 (TGF-β1) pathway associated with the appearance of myofibroblasts and the accumulation of ECM. The TGF-β1/Smad pathway plays a key role in the remodeling of intestinal tissue in DM [ 106 ]. On the other hand, in patients with vascular complications (inclu

Wound healing is a process carried out by re-epithelialization and is based on two functions: proliferation and cell migration [ 121 ]. The process of wound healing is governed by complex interactions between proteins and the ECM, involving a range of signaling pathways [ 122 ]. MMPs are involved in all wound-healing events. The functions of these are diverse and are not only involved in changes of the ECM. For example, during inflammation, neutrophils infiltrate the wound to protect against infection and release MMP-8, which is required for debridement of the wound and to cleave damaged collagen type I. In vivo studies show that MMP-8 deficiency leads to TGF-b signaling, inflammation, and delayed wound healing [ 123 ]. In injured skin, MMP-1 production is induced by keratinocytes that bind to type I collagen in the dermis through α2 and β1 integrins [ 30 ]. The proper functioning of MMP-1 is necessary for the migration of keratinocytes into type I collagen. This inductive response is controlled by the α2β1 integrin on migrating cells [ 124 ]. MMP-2 and MMP-9 play important roles in the cell migration involved in wound healing. Normally, MMP-2 participates in the proteolysis of laminin-5 during the phase of prolonged remodeling, which modulates the migration of keratinocytes to the final stage of wound healing [ 125 ]. MMP-1, MMP-2, and MMP-9 also contribute to wound re-epithelialization by loosening the tight contacts that keratinocytes initially establish with the dermal matrix. MMP-1 also takes part in the reduction of normal and hypertrophic scars [ 29 ]. The breaking of laminin-5 by MMP-2 promotes the cell migration of epidermal cells [ 126 ]. MMP-9 is upregulated by TGF-β through the activation of ligands of TGF-β and maintenance of the generation of keratinocyte migration [ 127 ]. In adiabetic patients, wound healing is known to require a balance between the accumulation of collagenous and non-collagenous ECM components and their remodeling by MMPs and TIMPs. MMP-8 and MMP-9 are involved in wound-healing events, and their physiological functions are the degradation of damaged type I collagen and the facilitation of keratinocyte migration. In addition, under the microenvironment of hypoxia and inflammation that is generated in diabetic foot ulcers (DFUs), the production of ROS increases, maintaining an upregulation of MMP-9, which damages the tissue and leads to poor wound healing [ 111 ]. MMP-8 also plays a role in the wound healing response, and MMP-9 is part of the physiopathology of DFUs [ 128 ]. New treatment strategies for healing chronic DFUs could be directed toward reducing concentrations of MMPs and increasing concentrations of TIMPs [ 129 ]. Compared with healing in normal patients, the combination of MMPs and decreased concentrations of TIMP-2 in chronic DFUs suggests that an increased proteolytic environment contributes to the failure of healing in the wounds of diabetics [ 129 ]. Infection is a major cause of diabetic foot syndrome, being aggravating by the increased burden of multi-resistant microorganisms. In DFU treatment, there is a decrease in the concentration of local IL-6, followed by a fall in MMP-9 and an increase in TIMP-1, resulting in better healing and a reduction in wound size [ 64 ]. For example, in a randomized, double-blind, placebo-controlled pilot study, the extract of Quercus robur (Robuvit ® ) considerably reduced oxidative stress and MMP-9 activity in patients after hysterectomy, improving the condition of the patients [ 130 ].

MMPs and TIMPs are involved in physiological processes such as neurogenesis, oligodendrogenesis, and cerebral plasticity [ 146 ]. They are essential for brain development due to their associations with neurophysiological functions. Furthermore, MMPs fulfill important functions in the central nervous system (CNS) during growth and development. They have important roles during the neuronal damage generated in acute and chronic conditions, as well as in neuronal repair processes [ 147 , 148 ]. In the CNS, the ECM includes proteoglycans involved in the development, survival, and activity of neuronal cells among its components. Neurodegenerative diseases are characterized by the death of neurons in different regions of the nervous system and consequent functional deterioration. MMP-2 and MMP-9 are expressed by neurons, astrocytes, and microglia in the CNS, and they play a physiopathological role in the disruption of the blood–brain barrier (BBB) through microglia activation and further progression of inflammatory cells [ 149 ]. The abnormal modulation of MMPs also participates in the pathogenesis of multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) [ 131 ]. The inhibition of MMPs has been proposed as a possible therapeutic strategy for the treatment of neurodegenerative diseases [ 48 ]. The mechanisms of action by which MMPs contribute to the aggravation of neurodegenerative diseases are slowly starting to be elicited. It has been shown that MMPs participate in a common pathway related to the pathological changes in CNS homeostasis, that is, the accumulation of pro-inflammatory molecules or aggregates of proteins and peptides, leading to the increased permeability of the CNS barrier and, therefore, to cell death [ 48 ]. In an intriguing genetic correlation between TIMPs and the nervous system, three of the genes encoding TIMPs occur within introns of genes encoding synapisins. The TIMP-1 gene resides within the SYNAPSIN-1 gene, the TIMP-3 gene resides within the SYNAPSIN-3 gene, and the TIMP-4 gene resides within the SYNAPSIN-2 gene. TIMP-2 is expressed in post-mitotic neurons and promotes neurite outgrowth and the differentiation of cells [ 150 ] as a result of cell cycle arrest through increased production of the cyclin-dependent kinase inhibitor p21Cip and decreased expression of cyclins B and D. In in vitro models, TIMP-2 expression has been found in α3 integrin-positive cells, suggesting that TIMP2-α3β1 integrin interactions participate in neurogenesis [ 151 ]. TIMP-1 is considered to be a candidate gene related to plasticity, whose expression increases greatly in the hippocampus [ 152 ]. Studies show that the absence of TIMP-1 leads to significant deterioration in the formation and recall of reward associations [ 153 ]. This effect is probably mediated by an effect on neuronal development and not by the direct action of TIMP-1 on the memory. 4.4.1. Multiple Sclerosis Multiple sclerosis, also known as demyelinating myelopathy, is a disease characterized by the appearance of demyelinating, neurodegenerative, autoimmune, inflammatory, and chronic CNS lesions [ 48 ]. The disability seen in MS is related to axonal damage and the loss of neuronal cells. MS is approximately 3-fold more common in women. The age of onset is typically between 20 and 40 years of age [ 154 ]. Well-established risk factors for MS include a genetic predisposition, vitamin D deficiency, Epstein–Barr virus exposure after early childhood, and cigarette smoking [ 89 ]. The human leukocyte antigen (HLA) association, first described in the early 1970s, suggests that MS is an autoimmune disease [ 155 ]. The strongest susceptibility signal maps to the HLA-DRB1 gene in the class II region of the major histocompatibility complex (MHC), which accounts for ≈10% of the disease risk. The lesions that occur in MS begin with perivenular cuffing by inflammatory mononuclear cells, predominantly macrophages and T-lymphocytes, which infiltrate the surrounding white matter. At sites of inflammation, the BBB is disrupted, while the vessel wall is preserved [ 156 ]. The involvement of the humoral immune system is evident, and the complement is activated by myelin-specific autoantibodies that are present on degenerating myelin sheaths. Demyelination is a pathological hallmark and is found at the earliest time points of tissue injury [ 157 ]. Accordingly, in MS, the imbalance of MMPs and TIMPs cause a series of effects that cause blood–brain barrier breakdown and the infiltration of peripheral blood leukocytes, which is followed by degradation of the myelin and, subsequently, axonal disruption and neuronal cell loss [ 158 ]. Various brain and immune cells can secrete MMPs. The expression of MMP-7 and MMP-9 has been observed in blood vessels of active lesions, MMP-3 has been observed in endothelial cells, and MMP-1, MMP-2, MMP-3, and MMP-9 are found around active and necrotic lesions [ 48 ]. It has been proposed that MMP-9 is secret

Alzheimer’s disease, also called senile dementia of Alzheimer’s type, is the main cause of dementia and is a great healthcare challenge. Approximately 10% of all persons aged >70 years have significant memory loss, and in more than half of these people, the memory loss is caused by AD. Patients present with a loss in episodic memory, followed by slowly progressive dementia [ 89 ]. Brain atrophy is caused by the death of neuronal cells and a decrease in the presence of dendrites in the cerebral cortex and other subcortical areas. In addition, amyloid plaques and neurofibrillary tangles that are linked to cerebral atrophy are present. One of the characteristics that distinguishes this disease is the formation of abnormal amyloid-β (Aβ) oligomers and abnormally phosphorylated tau proteins that are added to the amyloid plaques, which could be the main cause of neuronal dysfunction [ 174 ]. Aβ is a protein derived proteolytically from a larger transmembrane protein. It is known as amyloid precursor protein (APP) [ 175 ]. The APP has neurotrophic and neuroprotective properties. The plaque core is surrounded by a halo, which contains dystrophic tau-immunoreactive neurites and activated microglia. The accumulation of Aβ in cerebral arterioles is termed amyloid angiopathy [ 176 ]. Neurofibrillary tangles are composed of neuronal cytoplasmic fibrils. Tau binds to and stabilizes microtubules, supporting the axonal transport of glycoproteins, organelles, and neurotransmitters throughout the neuron [ 177 ]. Once hyperphosphorylated, tau cannot bind properly to microtubules and redistributes from the axon throughout the neuronal cytoplasm and distal dendrites, compromising function. Other theories emphasize that abnormal conformations of tau induce the misfolding of native (unfolded) tau into pathological conformations and that this prion-like templating process is responsible for the spread of tau [ 178 ]. Excess production of Aβ42 oligomers is a key initiator of cellular damage in AD [ 89 ]. The remodeling of the pericellular environment by MMPs is regulated by modulation of their actions on neurotransmitters, growth factors, receptors, and other cell surface components, such as adhesion molecules. One of the factors opposing the ability of MMPs to maintain the stability of the structures is the degradation of the APP. This protein that is degraded by the MMPs generates the segregation of Aβ peptides, which are poorly processed. These peptides are considered to be mainly responsible for AD, generating the inflammatory component of the disease and, as a consequence, greater damage (induced by neuroinflammation) is generated at the cerebral level [ 48 ]. Astrocytes are CNS cells that are associated with the activity of neurons and neurotransmitters, causing synaptic transmission and neurovascular coupling [ 179 ]. MMP-2 and MMP-9 are expressed in astrocytes [ 180 ], and the expression of Aβ regulates the levels of MMPs secreted in the extracellular compartment, causing degradation [ 181 ]. The levels of MMP-2 and MMP-9 are significantly elevated in the presence of neuronal lesions [ 182 ]. The expression of MMP-2 and MMP-9 is stimulated by Aβ, and these proteins are secreted by astrocytes [ 183 ] and pro-inflammatory cytokines, such as IL-1β. [ 184 ]. MMP-2 is individually detected in CNS structures, such as the spinal cord, astroglia, and pyramidal neurons in the cortex and Purkinje cells in the external granular layer of the cerebellum. Increased expression of MMP-2 has been observed in astrocytes around the senile plaques of transgenic mice. This MMP is released in its latent form (pro-MMP-2), which requires activation by means of MT1-MMP, in contrast with MMP-9, which is expressed in the spinal cord, cerebellum, hippocampus, and cortex, as well as predominantly in the neurons [ 185 ]. Studies have reported a reduction in OS through the inhibition of MMPs, particularly in cases of cerebral amyloid angiopathy, as seen in AD [ 186 ]. Aβ 25-35 was shown to cause changes in the expression of MMP-9 and TIMP-1, and these changes were correlated with neurotoxicity [ 187 ]. Several studies have shown that patients with AD have a higher MMP-9:TIMP-1 ratio and a lower level of TIMP-1 in the cerebrospinal fluid (CSF) compared with cognitively healthy elderly individuals, and the MMP-9:TIMP-1 ratio in patients with AD correlates with T-tau in the CSF, a marker of neuronal degeneration [ 188 ]. The proliferative effect of Aβ 25-35 is increased by the presence of TIMP-1, suggesting that TIMP-1 is mainly secreted by injured neurons and plays a role in astroglial reactivity. Thus, stimulation of the MMP-9:TIMP-1 pathway by Aβ 25-35 fragments may represent a self-defensive mechanism of elimination of amyloid deposition from brains with AD [ 189 ]. MMPs and their inhibitors (TIMP-1 and TIMP-2) play roles in impaired amyloid-β peptide metabolism, which is responsible for the genesis and progression of neurodegenerative dementia [ 190

Cardiovascular diseases (CVDs) are considered to be the top causes of morbidity and mortality around the world [ 206 ]. MMPs are involved in the development and progression of atherosclerosis and other CVDs; therefore, their alteration is related to increased risks of cardiovascular morbidity and mortality [ 207 ]. In CVDs, alterations in the degradation and regeneration of the ECM occur due to instability of the vascular wall secondary to the damage seen in this type of disease [ 207 ]. MMPs have the ability to interact with different proteins intracellularly. MMP-2 is able to degrade a series of contractility-related myofilament proteins, causing a decrease in the Ca2+ sensitivity of myofilaments with subsequent contractile dysfunction, as seen in the scenario of ischemia–reperfusion [ 208 ]. The current literature surrounding the intracellular activities of MMPs focuses on their pathological roles, but little is known about their physiological functions in these contexts. After decades of study, we know that MMP-2, in particular, is abundant and actively retained within the cytoplasm [ 4 , 5 , 209 , 210 , 211 , 212 , 213 ], and MMP-2 participates in cardiac injury and repair [ 214 , 215 , 216 ]. It also can directly impair ventricular function in the absence of superimposed injury [ 216 ] and participates in uncharacterized physiological functions within the striated muscle, possibly in the maintenance of sarcomere proteostasis [ 4 ]. MMPs are considered important in cardiovascular diseases. MMPs are related to cardiovascular pathologies, such as aneurysm formation, coronary artery disease, myocardial infarction (MI), atherosclerosis, arterial hypertension, and heart failure (HF) [ 207 , 217 , 218 , 219 ]. TIMPs and MMPs play significant roles in tissue remodeling related to cardiac function [ 220 ]. TIMP-2 inhibits bFGF-induced endothelial cell proliferation, TIMP-3 inhibits cell proliferation and the migration of stimulated endothelial cells, and TIMP-4 inhibits endothelial cells. The use of inhibition by TIMPs as a therapeutic tool for vascular disease is under development [ 221 ]. 4.5.1. Hypertension Clinically, according to the 2018 ESC/AHA guidelines for the management of arterial hypertension, hypertension is defined as a systolic blood pressure of more than 140 mmHg and a diastolic blood pressure of more than 90 mmHg. Epidemiologically, there is an overall prevalence of hypertension in adults of 30–45%. The presence of hypertension correlates with an increased risk of major cardiovascular events (hemorrhagic stroke, ischemic stroke, myocardial infarction, sudden death, heart failure, and peripheral artery disease) and end-stage renal disease [ 222 ]. The prevalence of hypertension is related to high dietary sodium intake, low dietary intakes of calcium and potassium [ 223 ], psychosocial stress, a low level of physical activity, and alcohol consumption [ 224 ]. In primary hypertension cases (95% of spontaneous cases), both non-innate (innate) and specific (adaptive) immune responses are activated. This leads to changes in the vascular walls in the microcirculation and then to chronic inflammation [ 129 ]. Inflammatory factors, such as C-reactive protein, IL-1β, IL-6, TNF-α, and ROS, are involved in the development and consolidation of hypertension by strengthening the stiffness of vessels and endothelial dysfunction [ 225 ]. MMP-2 and MMP-9 exhibit both pro- and anti-inflammatory properties. Elevated levels of MMP-9 and TIMP-1 in patients with essential hypertension are associated with increased arterial stiffness [ 226 ]. The activity of MMP-9 leads to the development of hypertension at an early stage, generating collagen degradation and arterial debilitation [ 227 ]. When an increase in blood pressure is generated, abnormal remodeling of the blood vessels occurs, and this later generates an overload of pressure in the cardiac muscle. MMP-9 plays a role in early-stage arterial remodeling in arteries, causing a rise in pressure through altered vessel distensibility. Under these conditions, vascular and cardiac tissue present additional compensatory remodeling, later leading to cardiac failure and other cardiovascular events [ 228 ]. As a result, the activity of MMPs increases during hypertension, which results in increased remodeling and progressive degradation of matrix components in the vascular wall; migration and proliferation of smooth muscle cells; and infiltration by monocytes [ 226 ]. Hypertension, as well as other inflammatory stimuli, has a double effect. On the one hand, it activates the T-lymphocytes, and on the other hand, it increases the production of chemokines and adhesion molecules in target tissues (heart, vascular, and renal), facilitating active access to pro-inflammatory cells [ 225 ]. Studies have shown elevated concentrations of TIMP-1 and MMP-9 in hypertensive subjects without HF and elevated levels of MMP-2 in hypertensive patients with HF [ 54 ]. TIMP-1 and MMP-1 are as

Type 1 MIs are characterized by plaque disruption with coronary atherothrombosis, causing posterior myocyte necrosis [ 243 ]. The balance between MMPs and TIMPs is important, as alterations to the ECM composition can contribute to alterations to myocardial structure or geometry [ 220 ]. MMPs play a role in plaque stability, as they counteract the thickening of the intimal layer; however, if this becomes excessive, it can lead to obstruction and ischemia. MMPs also lead to the destruction of the major components of the ECM, which causes plaque rupture [ 244 ]. The MI environment is characterized by inflammatory cells (mainly neutrophils), inflammatory mediators, and MMP-9, which is related to the physiopathology of post-MI ventricular remodeling and congestive HF [ 245 ]. Research has found that neutrophils are a source of MMP-9 [ 246 ]. MMP-9 has been found to participate in post-MI ventricular remodeling through impaired angiogenesis and tissue remodeling [ 247 ]. Nonetheless, the deletion of MMP-9 stimulates neovascularization in remodeling myocardium rather than decreasing it [ 248 ]. Altered balance in the interactions of MMPs and TIMPs has been shown to play a significant role in the development of many diseases, including tissue remodeling after MI [ 220 ]. MMPs are upregulated following the development of HF post-MI. They can release ECM fragments called matricryptins that are key during the development of heart failure post-MI. Studies have suggested that matricryptins could be potential therapeutic targets for heart failure patients [ 249 ]. Due to the critical role played by MMPs during cardiac remodeling, the identification of the biological systems responsible for ECM synthesis and degradation within the myocardium holds great relevance in the progression of HF. TIMPs impact post-myocardial infarction remodeling [ 250 ] and correlate positively with the left ventricular mass and wall thickness [ 251 ]. TIMP-1 correlates with the echocardiographic parameters of left ventricular (LV) dysfunction after acute MI [ 252 ]. Studies have shown that after myocardial infarction, TIMP-3 improves remodeling and myocardial function, promoting angiogenesis and inhibiting early proteolysis. This demonstrates the therapeutic potential of preserving the local equilibrium of TIMP-3 in the heart given its diverse functions in the modulation of different processes involved in adverse post-myocardial infarction remodeling [ 71 ]. The plasma TIMP-4 concentration, measured early after MI, may assist in the prediction of LV remodeling and, therefore, in the assessment of the prognosis [ 253 ]. Other studies have shown higher levels of TIMP-1, TIMP-2, and TIMP-4 in the plasma after AMI and are associated with major adverse cardiac events (MACEs) [ 65 ]. TIMP-2 deficiency accelerates adverse post-myocardial infarction remodeling because there is enhanced MT1-MMP activity, despite a lack of MMP-2 activation [ 250 ]. On the other hand, studies have shown that miR-17-3p increases the proliferation of cardiomyocytes and cell size by targeting TIMP-3 and acting upstream of the PTEN-AKT pathway. MiR-17-3p may represent a new therapeutic target to promote functional recovery after cardiac ischemia–reperfusion [ 254 ]. The imbalance between TIMPs and MMPs has been recognized as a factor that contributes to post-MI remodeling, so therapeutic strategies targeting this imbalance are necessary.

MMPs, cytokines, and growth factors intervene in physiological processes such as embryo implantation, trophoblast invasion and migration, and decidualization, with studies referring to blastocysts as being a direct source of MMP-2 [ 206 ]. Among the cytokines involved in decidualization, IL-11, which is produced by stromal and epithelial cells and increased by IL-1α, TNF-α, and TGF-β, induces the production of the human endometrium [ 274 ]. In addition to the involved cytokines, elevated levels of MMPs, such as MMP-2, MMP-3, and MMP-9, expressed in the decidua are associated with an increase in trophoblast invasion [ 41 ]. The presence of MMPs, along with gonadotropin chorionic hormone and VEGF, allows for modifications to the endometrium that are required for human implantation to occur, as well as playing a role in the prevention of abnormal pevelopment of the placenta [ 41 , 275 ]. MMPs and TIMPs control the site and remodeling of ovarian tissue and are associated with a variety of physiological and pathological processes. The correct balance between MMPs and their inhibitors plays a large role in the structural and functional vascular changes of women with complicated pregnancies [ 276 ]. 4.6.1. Polycystic Ovarian Syndrome Polycystic ovarian syndrome (PCOS) is the most common disorder of endocrine origin in women of reproductive age. Its clinical expression commonly includes oligo/anovulation, hyperandrogenism (clinical or biochemical), and the presence of polycystic ovaries, and it has a stretch relationship to insulin resistance, diabetes mellitus type 2, obesity, cardiovascular disease, and cancer risk [ 277 ]. PCOS is one of the most common causes of anovulatory infertility and affects 6–10% of premenopausal women. For diagnosis, adrenal and pituitary disorders must be excluded, and the counting of primordial follicles is also important [ 278 ]. PCOS has an important incidence in young women, and it can be underdiagnosed due to greater levels of follicles. Its etiology is not clear, but there is evidence of a genetic factor that affects patients during oogenesis [ 279 ]. The increasing levels of androgens that are seen in PCOS patients lead to insulin resistance in these patients, activating the synthesis of androgens and LH production, suppressing the synthesis of the sex hormone binding globulin, and stimulating adrenal and androgen biosynthesis related to anovulatory cycles [ 280 ]. Studies have investigated MMP-2 and MMP-9 expression in the ovaries [ 281 ]. Elevated concentrations of MMP-9 have been reported in women with PCOS that are related to the occurrence of angiogenesis and endothelial dysfunction seen in PCOS, as well as normal functions such as follicular growth, ovulation, and establishment of the luteal corpus [ 282 ]. One of the histological characteristics of PCOS is follicular atresia and the formation of ovarian cysts. MMP-9 is related to an imbalance in the excessive reconstruction of the ovarian follicles and walls, causing irregular ovulation, follicular occlusion, and an increase in stromal tissue [ 283 ]. TIMP-1, TIMP-2, and TIMP-3 are located in the stroma and teak of developing follicles. In addition to serum concentrations of MMP-9, MMP-9:TIMP-1 ratios are significantly higher in women with PCOS than in healthy women [ 284 ]. An altered balance between serum levels of MMPs and TIMPs in women with PCOS has recently been reported. Namely, there is a decrease in the serum level of TIMP-2, and the proportions of MMP-9 to TIMP-1 and MMP-2 to TIMP-2 increase significantly [ 68 ]. TIMP-1 levels may especially reflect both systemic chronic inflammatory and immune responses. Increased levels of MMP-8 and the MMP-8:TIMP-1 ratio in saliva and serum seem to be more pronounced in women with PCOS, and they are potentiated by gingival inflammation [ 285 ]. In addition, studies have shown that testosterone levels correlate positively with the proportion of MMP-9 to TIMP-1 and they correlate negatively with TIMP-2 [ 286 ]. It can be assumed that excessive androgen secretion can alter the balance of MMPs and TIMPs in the ovaries under physiological conditions, resulting in the progression of fibrosis in patients with PCOS [ 287 ]. Repression of the MMP-9:TIMP-1 ratio may have an important modulatory effect on progesterone secretion [ 288 ]. On the other hand, other studies have shown that the concentration of TIMP-3 mRNA is significantly lower in polycystic ovaries. The alterations observed in the production and/or distribution of type IV collagen and TIMP-3 suggest the involvement of the basement membranes in the pathogenesis of PCOS [ 72 ]. High levels of TIMP-1 have been seen in PCOS patients, and women who achieve pregnancy have higher TIMP-1 levels [ 66 ].

Preeclampsia (PE), as part of hypertensive disorders in pregnancy, is considered a serious complication worldwide. It is characterized by new-onset hypertension in the second half of pregnancy accompanied by proteinuria or thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and cerebral or visual symptoms. These symptoms are due to poor placentation that results in vascular dysfunction and major cardiovascular complications [ 303 ]. MMPs are associated with both implantation of the embryo and invasion of the trophoblast into the endometrium and inner myometrium. Therefore, a deregulation of MMP activity is related to abnormal placentation and vascular dysfunction, as seen in PE [ 304 ]. During the first weeks of pregnancy, MMPs begin preparing an adequate environment in the placental bed. The concentrations of MMP-2 and MMP-9 are maintained throughout pregnancy with the main function being to intervene during implantation and carry out trophoblastic invasion (MMP-9) and maintenance of the placental bed (MMP-2) [ 305 ]. The invasion of trophoblastic cells is led by autocrine and paracrine stimuli from the uterine and trophoblastic cells. In addition, several molecules that have been implicated in PE development, such as proteinases, cytokines, and growth factors, play roles in the excessively shallow invasion of the trophoblast seen in the physiopathology of PE, causing disturbed and inadequate remodeling of spiral arteries and thus reducing blood flow to the intervillous space, leading to systemic hypertension and fetal hypoxia [ 306 ]. In a study by Plaks et al., a mouse model of PE was reproduced by inactivating maternal and embryonic MMP-9, demonstrating a requirement for properly balanced MMP-9 activity in normal placentation [ 307 ]. Decreased MMP-2 and MMP-9 expression/activity leads to decreased vasodilation, increased vasoconstriction, and inadequate remodeling of uterine spiral arteries, resulting in impaired perfusion of the fetus–placental unit, leading to the secretion of factors within the maternal circulation and the establishment of endothelial dysfunction [ 308 ]. Studies have found increased MMP-2 activity/levels in patients with PE, as it can promote platelet aggregation, vascular remodeling, and the release of vasoactive peptides, such as entothelin-1. These concentrations have been shown to be mediated by vascular endothelial growth factor (VEGF) [ 309 ]. MMP-1 is elevated in women with PE, but without an increase in TIMP-1. It is involved in the degradation of vascular collagen type I, which increases vascular permeability and favors edema and proteinuria, which are features observed in patients with PE. There is a stretch relationship between the neutrophil activation, migration, and vascular dysfunction seen in PE, as MMP-1 has roles in leukocyte migration and vascular dysfunction; likewise, its expression is induced by activated neutrophils, which also generate ROS and TNF-α [ 310 ]. The levels of MMPs in the urine, particularly MMP-2, have been postulated as predictive biomarkers for patients at high risk for PE between 12 and 16 weeks of gestation. This shows that an existing imbalance of MMPs in pregnancy can affect the vasculature at structural and functional levels, with detectable changes occurring before the disease and its clinical signs appear [ 311 ]. The controlled expression and proper balance between MMPs and TIMPs, which determine the net MMP activity and hence regulate the invasive potential of placental trophoblasts, are pivotal for maintaining normal placentation [ 312 ]. In general, any imbalance in this equilibrium can lead to the development of pathological conditions, and specifically, during pregnancy, this imbalance disturbs the trophoblastic invasive cascade [ 298 ]. TIMP-1 is a major endogenous inhibitor of MMP-9 that may affect the responsiveness of hypertensive disorders of pregnancy to therapy [ 313 ]. TIMP-1 is elevated in PE [ 314 ]. Studies in placentas from pregnant women diagnosed with PE have shown that at the transcriptional level, the abnormal expression of TIMP-1 can cause insufficient trophoblastic invasion and superficial placentation [ 315 ]; However, other studies have shown reduced MMP-1 levels in the umbilical serum, placenta, and decidua in women who have developed PE [ 316 ]. TIMP-2 levels are higher in women who develop a hypertensive disorder [ 317 ]; however, the specific role of TIMP-2 in the disease is still unknown. TIMP-3 expression is markedly reduced in preeclamptic placentas, as TIMP-3 is an endogenous TACE inhibitor, and the downregulation of TIMP-3 activity in trophoblasts could result in increased TACE expression and subsequently lead to increased TNF-α production [ 318 ]. Histone deacetylases promote trophoblast cell migration and invasion by repressing the TIMP-3 promoter through histone hypoacetylation [ 319 ]. Furthermore, studies have shown that the TIMP-3 promoter is hypomethylated in the pla

Inflammation is a hallmark of many chronic and autoimmune diseases, including cancer, rheumatoid arthritis (RA), osteoarthritis (OA), psoriasis, and chronic obstructive pulmonary disease (COPD), among others. MMPs and TIMPs play key roles in the self-regulation of inflammation in these diseases [ 399 , 400 ] ( Figure 4 ). OA is the most prevalent arthritic disease affecting the joints. It is a degenerative disease characterized by chronic joint pain, inflammation, and damage to the joint cartilage [ 401 ]. The articular cartilage is made up of type II collagen and proteoglycan aggregates. The integrity of the joint structure is dependent on these aggregates. MMP-13 is expressed by chondrocytes in human osteoarthritic cartilage, and it plays a key role in the degradation of type II collagen in bone and cartilage [ 402 ]. In patients with OA, variable levels of MMP-13 mRNA have been observed in osteoarthritic cartilage samples. The expression of both MMP-13 and MMP-1 in cartilage was significantly induced at both the mRNA and protein levels by interleukin-1a. Recombinant MMP-13 cleaved type II collagen, and MMP-13 turned over type II collagen at least 10 times faster than MMP-1 [ 403 ]. In OA models using samples of cartilage and human primary chondrocytes stimulated with IL-1β and TNF-α, the expression level of MMP-13 associated with degeneration in the joints and various inflammatory cytokines was measured. The involvement of MMP-13 in the pathogenesis of osteoarthritis was demonstrated by altering the physiological and anatomical functions of the joints [ 401 , 404 ]. The Akt signaling pathway and the activation of NF-κB signaling in chondrocytes are involved in the development of OA [ 405 ]. In OA, mononuclear cells (e.g., macrophages and T-cells) infiltrate the synovial membrane, and the levels of pro-inflammatory cytokines in synovial fluid and peripheral blood samples are elevated. Increased release of inflammatory mediators including IL-1β, IL-6, IL-8, IL-15, and TNF-α induces the expression of proteolytic enzymes such as MMPs, resulting in cartilage breakdown [ 406 ]. RA is an autoimmune disease of connective tissue that is characterized by destruction of the joint cartilage and, subsequently, of the under-lying bone [ 407 ]. MMPs and TIMPs have significant roles in ECM degradation associated with tissue damage in inflammation and RA. In vivo studies have shown elevated expression of MMP-2, MMP-3, and MMP-9 in RA. These enzymes break down the components of the non-collagenous matrix of the joints [ 408 ]. MMP-1 and MMP-13 have predominant roles in RA because they limit the rate of the collagen degradation process. In addition to collagen, MMP-13 degrades aggrecan and proteoglycan, giving it a dual role in ECM destruction in RA [ 408 ]. In RA, TIMPs are abundantly expressed in inflamed synovia. Synovial fluid samples from patients with RA were assessed for their reactivity with recombinant TIMPs. The presence of antibodies was analyzed, and the results were compared with healthy subjects. It was found that RA patients developed an autoimmune response to TIMPs (TIMP-1, TIMP-2) [ 409 ]. TIMP-1 and TIMP-2 retard plaque initiation and the progression of early lesions [ 242 ]. In vivo studies have shown that the over-expression of TIMP-3 decreases the plaque size and increases features of stability such as an increased collagen content and decreased necrotic core size in RA [ 410 ]. Psoriasis is a chronic skin condition driven by the activated immune system [ 411 ]. In this disease, MMPs are involved in the structural changes of the epidermis through the modification of intracellular contacts and the composition of the ECM, promoting angiogenesis in the dermal blood vessels and the infiltration of immune cells. Studies have shown that MMP-13 and MMP-9 participate in keratinocyte migration, angiogenesis, and contraction in wound healing in murine models [ 412 ]. In psoriasis, TIMP-1 and TIMP-3 are present in the inflammatory infiltrate and in the endothelial cells of the papillary dermis. TIMP-3 is downregulated at both transcriptional and protein levels in the epidermal keratinocytes associated with psoriatic lesions compared with respective healthy controls [ 413 ]. The levels of the TIMP1 protein in the blood serum increase after the occurrence of a psoriasis rash to a degree that correlates with the severity of the disease [ 414 ]. Another example of protease−antiprotease imbalance in the development of inflammatory disease occurs in COPD, which is a group of progressive lung diseases, most commonly emphysema and chronic bronchitis [ 415 ]. In a previous study, Uysal et al. classified patients with COPD by the severity of symptoms and risk of exacerbation, and they found that elevated plasma levels of MMP-9, TIMP-1, and TIMP-2 correlated with the severity of disease. The MMP-9 concentration and the MMP-9/TIMP-1 ratio were higher in patients with emphysema than in those with other phenotypes. This and ot

To date, no accurate therapy based on MMP inhibition has been made available for clinical use in chronic diseases, so new strategies are needed to make proper use of the benefits provided by the known mechanisms of MMPs and TIMPs. The inhibition of MMP secretion and/or function in the correct place with the purpose of providing a better quality of life to those patients who have an illness related to the deregulation of MMPs may have advantages. It is necessary to continue basic research to explore the roles of MMPs involved in most of the diseases mentioned in this review, as has been the case for MMP-2 and MMP-9. It is known that the functions of MMPs are difficult to predict; however, by knowing the mechanisms of action by which they contribute to the aggravation of diseases, they can have benefits, not only as therapies but also as biomarkers and risk predictors of disease. According to the present review, it is clear that there is great heterogeneity in the status of TIMPs depending on the different diseases, because these differ in the types of interactions that they undergo with the distinct MMPs, as well as independently of MMPs. However, a generalized increase in TIMP-1 and a generalized silencing of TIMP-3 can be observed as disease progresses and the prognosis worsens. Additional studies are necessary for the specific investigation of these endogenous inhibitors in different chronic diseases. An alternative approach to the therapy of MMP-related diseases could be to use engineered TIMPs with restricted inhibitory specificities. It is necessary to broaden our knowledge on the specific roles of MMPs and TIMPs through studies and analyses focused on evaluating the activity of MMPs at the post-translational level, since most studies in the literature have only evaluated transcriptional activity, and there is little information on the intracellular activity of MMPs to rule out relevant functions of pathological importance that could provide more information on the different roles of MMPs and TIMPs in the different diseases mentioned in this review. It is also necessary to conduct more in vivo studies to demonstrate the functional activity of MMPs and TIMPs because it is not yet possible to elucidate how they are regulated/deregulated and to determine which substrates interfere in the different processes. Additional analyses are required to assess MMP activity under pathological and non-pathological conditions. We consider it necessary to emphasize the aforementioned points in order to carry out future research that will allow us to expand our knowledge and delve deeper into this field of study.