Plasma Levels of MMPs and TIMP-1 in Patients with Osteoarthritis After Recovery from COVID-19.

BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPS) play a key role in the pathogenesis of osteoarthritis (OA). Recent research showed the involvement of some MMPs in COVID-19, but the results are limited and contradictory. OBJECTIVE: In this study, we investigated the levels of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10) and TIMP-1 in the plasma of patients with OA after recovery from COVID- 19. METHODS: The experiment involved patients aged 39 to 80 diagnosed with knee OA. All study participants were divided into three research groups: the control group included healthy individuals, the group OA included patients with enrolled cases of OA, and the third group of OA and COVID-19 included patients with OA who recovered from COVID-19 6-9 months ago. The levels of MMPs and TIMP-1 were measured in plasma by enzyme-linked immunosorbent assay. RESULTS: The study showed a change in the levels of MMPs in patients with OA who had COVID- 19 and those who did not have a history of SARS-CoV-2 infection. Particularly, patients with OA who were infected with coronavirus established an increase in MMP-2, MMP-3, MMP-8, and MMP-9, compared to healthy controls. Compared to normal subjects, a significant decrease in MMP-10 and TIMP-1 was established in both groups of patients with OA and convalescent COVID-19. CONCLUSION: Thus, the results suggest that COVID-19 can affect the proteolysis-antiproteolysis system even after a long postinfectious state and may cause complications of existing musculoskeletal pathologies.

Matrix metalloproteinases in COVID-19: underlying significance

The role of matrix metalloproteinases (MMPs) in pathogenesis and severity of coronavirus disease 2019 (COVID-19) is under extensive exploration. MMPs are a family of extracellular proteases involved in a variety of physiological and pathological processes and conditions. The role of MMPs in COVID-19 stems from the pathogenesis resulting in the release of chemokines and pro-inflammatory markers which cause pulmonary oedema. In addition, the approaches to treatment of COVID-19 often are associated with some complications like acute lung injury due to extracellular matrix remodelling. In this respect, the aim of this review is to summarize, interpret and evaluate the significance of matrix metalloproteinases in SARS-CoV-2 infection in terms of the severity of the condition and delve into potential treatment from this perspective as well as highlighting the physiological and protective role of some MMPs. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Possible Role of Matrix Metalloproteinases and TGF-ß in COVID-19 Severity and Sequelae.

The costs of coronavirus disease 2019 (COVID-19) are devastating. With millions of deaths worldwide, specific serological biomarkers, antiviral agents, and novel therapies are urgently required to reduce the disease burden. For these purposes, a profound understanding of the pathobiology of COVID-19 is mandatory. Notably, the study of immunity against other respiratory infections has generated reference knowledge to comprehend the paradox of the COVID-19 pathogenesis. Past studies point to a complex interplay between cytokines and other factors mediating wound healing and extracellular matrix (ECM) remodeling that results in exacerbated inflammation, tissue injury, severe manifestations, and a sequela of respiratory infections. This review provides an overview of the immunological process elicited after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Also, we analyzed available data about the participation of matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-ß) in immune responses of the lungs. Furthermore, we discuss their possible implications in severe COVID-19 and sequela, including pulmonary fibrosis, and remark on the potential of these molecules as biomarkers for diagnosis, prognosis, and treatment of convalescent COVID-19 patients. Our review provides a theoretical framework for future research aimed to discover molecular hallmarks that, combined with clinical features, could serve as therapeutic targets and reliable biomarkers of the different clinical forms of COVID-19, including convalescence.

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children.

Introduction: Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases. Methods: To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations). Results: Children with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84-100% and specificity 80-100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels. Discussion: Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.

Neuro-Axonal Damage and Alteration of Blood-Brain Barrier Integrity in COVID-19 Patients.

Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood-brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization.

Targeting inflammation with collagen.

Tissue damage caused by an infection oran autoimmune disease triggers degradation of collagen in the extracellular matrix (ECM), which further enhances inflammation. Therefore, improving ECM in aninflamed tissue can be exploited as a potential therapeutic target. A recentstudy emphasised an innovative approach against COVID-19 using polymerised type I collagen (PTIC) that improves disease severity through a hitherto unknownmechanism. In this paper, we provide an overview of potential mechanism thatmay explain the anti-inflammatory effect of collagen peptides. In addition,the paper includes a brief summary of possible side effect of collagendeposition in inflammatory diseases. Altogether, current knowledge suggeststhat collagen may potentially reduce the residual risk in inflammatorydiseases; however, the detailed mechanism remains elusive.

Repurposing Based Identification of Novel Inhibitors against MmpS5-MmpL5 Efflux Pump of Mycobacterium smegmatis: A Combined In Silico and In Vitro Study.

In the current era of a pandemic, infections of COVID-19 and Tuberculosis (TB) enhance the detrimental effects of both diseases in suffering individuals. The resistance mechanisms evolving in Mycobacterium tuberculosis are limiting the efficiency of current therapeutic measures and pressurizing the stressed medical infrastructures. The bacterial efflux pumps enable the development of resistance against recently approved drugs such as bedaquiline and clofazimine. Consequently, the MmpS5-MmpL5 protein system was selected because of its role in efflux pumping of anti-TB drugs. The MmpS5-MmpL5 systems of Mycobacterium smegmatis were modelled and the virtual screening was performed using an ASINEX library of 5968 anti-bacterial compounds. The inhibitors with the highest binding affinities and QSAR based highest predicted inhibitory concentration were selected. The MmpS5-MmpL5 associated systems with BDE_26593610 and BDD_27860195 showed highest inhibitory parameters. These were subjected to 100 ns Molecular Dynamics simulations and provided the validation regarding the interaction studies. The in vitro studies demonstrated that the BDE_26593610 and BDD_27860195 can be considered as active inhibitors for M. smegmatis MmpS5-MmpL5. The outcomes of this study can be utilized in other experimentation aimed at drug design and discovery against the drug resistance strains of M. tuberculosis.

Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development.

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%->50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control-case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.

SARS-CoV-2 and pathological matrix remodeling mediators.

BACKGROUND: Recognizing only sharp elevation in a short period of time, the COVID-19 SARS-CoV-2 propagation is more and more marked in the whole world. Induced inflammation afterwards infection engenders a high infiltration of immune cells and cytokines that triggers matrix metalloproteinases (MMPs) activation. These endopeptidases are mediators of the lung extracellular matrix (ECM), a basic element for alveoli structure and gas exchange. METHODS: When immune cells, MMPs, secreted cytokines and several other mediators are gathered a pathological matrix remodeling occurs. This phenomenon tends to tissue destruction in the first place and a pulmonary hypertrophy and fibrosis in the second place. FINDINGS: After pathological matrix remodeling establishment, pathological diseases take place even after infection state. Since post COVID-19 pulmonary fibrosis is an emerging complication of the disease, there is an urge to better understand and characterize the implication of ECM remodeling during SARS-CoV-2 infection. CONCLUSION: Targeting MMPs and their inhibitors could be a probable solution for occurred events since there are many cured patients that remain with severe sequels even after the end of infection.

Interleukin-1ß Modulation of the Mechanobiology of Primary Human Pulmonary Fibroblasts: Potential Implications in Lung Repair.

Pro-inflammatory cytokines like interleukin-1ß (IL-1ß) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1ß on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1ß and used Atomic Force Microscopy to unveil that IL-1ß significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1ß stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1ß may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1ß-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1ß provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair.