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The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors.

ABSTRACT: Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat^®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches, such as proteomics and N-terminomics, to identify new MMP substrates. We present some examples of new MMP substrates and their implications in regulating biological functions. By characterizing the roles and substrates of individual MMP, MMP inhibitors could be utilized more effectively in the optimal disease context or in diseases never tested before where MMP activity is elevated and contributing to disease progression.

SUBMITTER: Das N

PROVIDER: S-EPMC7823758 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors.

Das Nabangshu N Benko Colette C Gill Sean E SE Dufour Antoine A

Pharmaceuticals (Basel, Switzerland) 20201231 1

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat<sup>®</sup>, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examp ...[more]

PMID: 33396445

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Project description:Cardiac amyloidosis due to amyloid fibril deposition in the heart results in cardiomyopathy (CMP) with heart failure (HF) and/or conduction disturbances. Immunoglobulin light chain-related CMP (AL-CMP) features rapidly progressive HF with an extremely poor prognosis compared with a CMP due to the deposition of mutant (ATTR) amyloidosis or wild-type (senile systemic amyloidosis, SSA) transthyretin (TTR) proteins. Amyloid fibril deposition disrupts the myocardial extracellular matrix (ECM) homeostasis, which is partly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). We therefore tested the hypothesis that circulating levels of MMPs and TIMPs in patients with AL-CMP and TTR-related CMP (TTR-CMP) are dissimilar and indicative of cardiac amyloid disease type.Fifty AL-CMP patients were compared with 50 TTR-CMP patients (composed of 38 SSA and 12 ATTR patients). Clinical and laboratory evaluations including echocardiography were performed at the initial visit to our center and analyzed. Serum MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were determined by ELISA. Compared with TTR-CMP patients, AL-CMP patients had higher levels of brain natriuretic peptide (BNP), troponin I (TnI), MMP-2, TIMP-1, and MMP-2/TIMP-2 ratio, despite less left ventricular (LV) hypertrophy and better preserved LV ejection fraction. Mortality was worse in AL-CMP patients than in TTR-CMP patients (log-rank P<0.01). MMP-2/TIMP-2 plus BNP and TnI showed the highest discriminative ability for distinguishing AL-CMP from TTR-CMP. Female sex (HR, 2.343; P=0.049) and BNP (HR, 1.041; P<0.01) were predictors for mortality for all patients with cardiac amyloidoses. Only BNP was a predictor of death in AL-CMP patients (HR, 1.090; P<0.01). There were no prognostic factors for all-cause death in TTR-CMP patients.Circulating concentrations of MMPs and TIMPs may be useful in differentiating patients with AL-CMP from those with TTR-CMP, resulting in earlier diagnostic vigilance, and may add prognostic information. In addition to an elevated BNP level, female sex increased the risk of death in patients with cardiac amyloidoses.

Project description:OBJECTIVE:Turnover of cartilage endplate extracellular matrix (ECM) may play an important role in disc degeneration and low back pain (LBP). However, the expression pattern of pro-inflammatory factors, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) in the cartilage endplates (CEP) of intervertebral discs (IVD) is not understood. We aimed to examine the transcriptional levels of MMP, TIMP, and interleukins (IL), and the correlations between them. METHODS:Thirty degenerated cartilage endplate samples from patients with LBP who underwent lumbar fusion surgery were included in the degenerated group. Ten patients without LBP history who underwent lumbar surgery because of vertebral burst fractures were included in the control group. The degenerative severity of the samples was evaluated by MRI, and hematoxylin-eosin and safranin O-fast green (SO-FG) staining. Real-time polymerase chain reaction (RT-PCR) was used to detect the mRNA levels of MMP-1, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, TIMP-3, IL-1?, IL-1?, and IL-6. The correlations between the levels of these genes were tested using Spearman's rho test. RESULTS:Hematoxylin-eosin and SO-FG staining confirmed a decrease in cell number and proteoglycans in the degenerated cartilage endplate. MRI showed significant signal changes in degenerated cartilage endplates. Patients in the degenerated group showed a higher rate of endplate Modic changes when compared with the control group. MMP-3, MMP-9, TIMP-3, IL-1?, and IL-1? were elevated with statistical significance, while MMP-1, MMP-13, TIMP-1, TIMP-2, and IL-6 were changed without statistical significance or remained unchanged. Expression of MMP-3 was positively correlated with IL-1? (Spearman coefficient, 0.486; P?< 0.05); expression of TIMP-3 was positively correlated with MMP-9, IL-1?, and IL-1? (Spearman coefficient, 0.577, 0.407, and 0.571, respectively; P?< 0.05). CONCLUSION:MMP-3, MMP-9, TIMP-3, IL-1?, and IL-1? may play a role in the process of cartilage endplate degeneration. MMP-3 may be regulated by IL-1?, and TIMP-3 might be associated with MMP-9 and regulated by IL-1? and IL-1?.

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The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors.

Publications

The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors.

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