Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mesenchymal stem cells (MSCs) can contribute to tissue repair by actively migrating to sites of tissue injury. However, the cellular and molecular mechanisms of MSC recruitment are largely unknown. The nuclear factor (NF)-kappaB pathway plays a pivotal role in regulating genes that influence cell migration, cell differentiation, inflammation, and proliferation. One of the major cytokines released at sites of injury is tumor necrosis factor-alpha (TNF-alpha), which is known to be a key regulator of the NF-kappaB pathway. Therefore, we hypothesized that TNF-alpha may lead to MSC invasion and proliferation by activation of the NF-kappaB pathway. TNF-receptor 1 and 2, NF-kappaB (p65), and IkappaB kinase 2 (IKK-2) are expressed in human MSCs (hMSCs). Stimulation of hMSCs with TNF-alpha caused a p65 translocation from the cytoplasm to nucleoplasm but did not change the expression profile of MSC markers. TNF-alpha strongly augmented the migration of hMSCs through the human extracellular matrix. Using lentiviral gene transfer, overexpressing a dominant-negative mutant of IKK-2 (dn-IKK-2) significantly blocked this effect. NF-kappaB target genes associated with migration (vascular cell adhesion molecule-1, CD44, and matrix metalloproteinase 9) were upregulated by TNF-alpha stimulation and blocked by dn-IKK-2. Moreover, using the bromodeoxyuridine assay, we showed that the inhibition of the NF-kappaB pathway caused a significant reduction in the basal proliferation rate. TNF-alpha stimulated the proliferation of hMSCs, whereas overexpression of dn-IKK-2 significantly blocked this effect. TNF-alpha led to the upregulated expression of the proliferation-associated gene cyclin D1. In conclusion, we demonstrated that the NF-kappaB pathway components, p65 and IKK-2, are expressed in hMSCs. Our data provide evidence that this signal transduction pathway is implicated in TNF-alpha-mediated invasion and proliferation of hMSCs. Therefore, hMSC recruitment to sites of tissue injury may, at least in part, be regulated by the NF-kappaB signal transduction pathway.
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PMID:IKK-2 is required for TNF-alpha-induced invasion and proliferation of human mesenchymal stem cells. 1860 Mar 6

The NF-kappaB signaling pathway is known to play an important role in the regulation of osteoclastic bone resorption and cancer cell growth. Previous studies have shown that genetic inactivation of IkappaB kinase (IKK), a key component of NF-kappaB signaling, inhibits osteoclastogenesis, but the effects of pharmacologic IKK inhibitors on osteolytic bone metastasis are unknown. Here, we studied the effects of the IKK inhibitors celastrol, BMS-345541, parthenolide, and wedelolactone on the proliferation and migration of W256 cells in vitro and osteolytic bone destruction in vivo. All compounds tested inhibited the growth and induced apoptosis of W256 cells as evidenced by caspase-3 activation and nuclear morphology. Celastrol, BMS-345541, and parthenolide abolished IL1beta and tumor necrosis factor alpha-induced IkappaB phosphorylation and prevented nuclear translocation of NF-kappaB and DNA binding. Celastrol and parthenolide but not BMS-345541 prevented the activation of both IKKalpha and IKKbeta, and celastrol inhibited IKKalpha/beta activation by preventing the phosphorylation of TAK1, a key receptor-associated factor upstream of IKK. Celastrol and parthenolide markedly reduced the mRNA expression of matrix metalloproteinase 9 and urinary plasminogen activator, and inhibited W256 migration. Administration of celastrol or parthenolide at a dose of 1 mg/kg/day suppressed trabecular bone loss and reduced the number and size of osteolytic bone lesions following W256 injection in rats. Histomorphometric analysis showed that both compounds decreased osteoclast number and inhibited bone resorption. In conclusion, pharmacologic inhibitors of IKK are effective in preventing osteolytic bone metastasis in this model and might represent a promising class of agents to the prevention and treatment of metastatic bone disease associated with breast cancer.
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PMID:Pharmacologic inhibitors of IkappaB kinase suppress growth and migration of mammary carcinosarcoma cells in vitro and prevent osteolytic bone metastasis in vivo. 1967 67

IkappaB kinase (IKK)-mediated intracellular signaling mechanisms may be involved in airway hyperresponsiveness through up-regulation of bradykinin receptors. This study was designed to examine if organ culture of rat bronchial segments induces airway hyperresponsiveness to bradykinin and if inhibition of IKK can abrogate the airway hyperresponsiveness to bradykinin via suppressing the expression of bradykinin B1 and B2 receptors. Rat bronchi were isolated and cut into ring segments. The segments were then organ cultured in the presence or absence of IKK inhibitors, BMS-345541 or TPCA-1. des-Arg9-bradykinin (B1 receptor agonist)--and bradykinin (B(2) receptor agonist)--induced contractions of the segments were monitored by a sensitive organ bath system. The expression of bradykinin B1 and B2 receptors, inflammatory mediators and phosphorylated IKK were studied by a real-time PCR and/or by immunohistochemistry using confocal microscopy. Organ culture of the bronchial segments induced a time-dependent up-regulation of bradykinin B1 and B2 receptors. The IKK inhibitors abolished the organ culture-induced up-regulation of bradykinin B1 and B2 receptor-mediated contractions in a concentration-dependent manner. This was paralleled with inhibition of IKK activity (phosphorylation), reduced mRNA and protein expressions of bradykinin B1 and B2 receptors and decreased mRNA expression of inflammatory mediators (interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2 and matrix metalloproteinase 9). Our results show that organ culture induces IKK-mediated inflammatory changes in airways which subsequently results in airway hyperresponsiveness to bradykinin via the up-regulated bradykinin receptors. Thus, IKK inhibition might be a promising approach for treatment of airway inflammation and airway hyperresponsiveness that are often seen in asthmatic patients.
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PMID:Up-regulation of bradykinin receptors in rat bronchi via I kappa B kinase-mediated inflammatory signaling pathway. 2018 74