Idiopathic pulmonary fibrosis (IPF), a fatal disease characterized by excessive matrix degradation and fibrosis, destroys the lung architecture and results in the inability of the lungs to absorb oxygen. The cause(s) of IPF is unknown and current treatments are palliative. Matrix metalloproteinases (MMPs) and A Disintegrin And Metalloproteinases (ADAMs) likely play roles in IPF progression. However, specific MMPs and ADAMs in IPF have not been identified due to challenges in MMP/ADAM profiling. We employed a designer affinity resin that binds exclusively to the active forms of MMPs and ADAMs and found by mass spectrometry higher levels of active MMP-1, ADAM9, ADAM10, and ADAM17 in lung tissues of IPF patients. Inhibition of MMP-1 and ADAM10 with the small-molecule inhibitor GI254023X in an in vitro lung fibrosis assay decreased the profibrotic protein α-smooth muscle actin (α-SMA). Our results indicate that inhibition of MMP-1 and ADAM10 may hold promise in treatment of IPF.
Pressure ulcers (PUs) are chronic wounds that lead to amputations and death. Little is known about why PUs are recalcitrant to healing. Wound healing is mediated by matrix metalloproteinases (MMPs). The 24 MMPs in humans each exist in three forms, of which only one is catalytically competent. We analyzed human PU samples using an affinity resin that exclusively binds to the catalytically competent MMPs. We identified by mass spectrometry the active forms of MMP-1, MMP-8, MMP-9, and MMP-14. Concentrations of MMP-8, MMP-9, and MMP-14 were higher in human PUs compared to the healthy tissue, whereas those for MMP-1 did not change. Decreasing levels of active MMP-9 as the PU improved argued for a detrimental role for this enzyme. In a mouse model of PUs, a highly selective inhibitor for MMP-9 and MMP-14, (R)-ND-336, accelerated wound closure in parallel with significant amelioration of ulcer stage. (R)-ND-336 holds promise as a first-in-class treatment for PUs.
There exists a paucity of information on the pathogenesis of pterygium, a benign ocular tumor that scars the cornea and can lead to vision loss. The main recourse for pterygium is surgery; however, recurrence is observed. Matrix metalloproteinases (MMPs) are involved in the pathology of pterygium. The determination of the specific MMP involved among the 24 human enzymes has not been established due to challenges in MMP profiling. We used an affinity resin that binds specifically to the active forms of MMPs in the complex mixture of the cellular proteome. The proteomics analysis identified active MMP-14 and three related metalloproteinases, ADAM9, ADAM10, and ADAM17, in human pterygia. Inhibition of MMP-14 with the small-molecule inhibitor (R)-ND-336 was assessed in cell migration and collagen contraction assays. (R)-ND-336 attenuated human conjunctiva fibroblast migration and mitigated collagen contraction, both activities required for the formation of pterygium. (R)-ND-336 holds the promise of a therapeutic recourse for pterygium as an orphan disease.
Background The median survival of Glioblastoma multiforme (GBM) patients is 14+ months due to poor responses to surgery and chemoradiation. Means to counteract radiation resistance are therefore highly desirable. we demonstrate the membrane-bound matrix metalloproteinase MT1-MMP promotes resistance of GBM to radiation, and that using a selective and brain permeable MT1-MMP inhibitor, (R) -ND336, improved tumor control can be achieved in preclinical studies. Methods Public microarray and RNA-sequencing data were used to determine MT1-MMP relevance in GBM patient survival. Glioma stem-like neurospheres (GSCs) were used for both in vitro and in vivo assays. An affinity resin coupled with proteomics was used to quantify active MT1-MMP in brain tissue of GBM patients. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP and inhibition via the MT1-MMP inhibitor (R) -ND336, were used to assess the role of MT1-MMP in radioresistance. Results MT1-MMP expression inversely correlated with patient survival. Active MT1-MMP was present in brain tissue of GBM patients but not in normal brain. shRNA- or (R) -ND336-mediated inhibition of MT1-MMP sensitized GSCs to radiation leading to a significant increase in survival of tumor-bearing animals. MT1-MMP depletion reduced invasion via the effector protease MMP2; and increased the cytotoxic response to radiation via induction of replication fork stress and accumulation of double strand breaks (DSBs), making cells more susceptible to genotoxic insult. Conclusions MT1-MMP is pivotal in maintaining replication fork stability. Disruption of MT1-MMP sensitizes cells to radiation and can counteract invasion. (R) -ND336, which efficiently penetrates the brain, is therefore a novel radiosensitizer in GBM.
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