Skip to main content

Advertisement

Log in

Induction of Matrix Metalloproteinase-3 (MMP-3) Expression in the Microglia by Lipopolysaccharide (LPS) via Upregulation of Glycoprotein Nonmetastatic Melanoma B (GPNMB) Expression

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Substantial evidence suggests that inflammation is an important contributor to many neurodegenerative disorders. Activated microglial cells play an important role in releasing pro-inflammatory factors, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) for inducing inflammation. Recently, some reports have suggested that glycoprotein nonmetastatic melanoma B (GPNMB) is highly expressed in microglia after LPS treatment. However, the role of GPNMB in activated microglia is not clearly understood. In this study, we used RT-PCR and Western blotting to detect GPNMB and matrix metalloproteinase-3 (MMP-3) expressions in activated microglia. GPNMB small interfering RNA (siRNA) or MMP-3 inhibitor was applied on microglial BV2 cells, and ELISA was performed to measure the expressions of TNF-α and IL-1β in BV2 cells. Levels of iNOS and NO in BV2 cells were also determined. We found that the levels of GPNMB and MMP-3 were significantly increased in BV2 cells after LPS treatment. Moreover, we found that GPNMB significantly upregulated the expression of MMP-3 in BV2 cells, and high expression of MMP-3 was dependent on the level of GPNMB. Inhibition of GPNMB or MMP-3 expression by GPNMB siRNA or MMP-3 inhibitor dramatically suppressed the expressions of TNF-α, IL-1β, iNOS, and NO in activated microglia. All of these results suggest that GPNMB is involved in the inflammatory responses of microglia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Carvey PM, Chang Q, Lipton JW, Ling Z (2003) Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson’s disease. Frontiers in bioscience: a journal and virtual library 8:s826–s837

    Article  CAS  Google Scholar 

  • Chung J-S, Sato K, Dougherty II, Cruz PD, Ariizumi K (2007) DC-HIL is a negative regulator of T lymphocyte activation. Blood 109:4320–4327

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Furochi H, Tamura S, Mameoka M, Yamada C, Ogawa T, Hirasaka K, Okumura Y, Imagawa T, Oguri S, Ishidoh K (2007) Osteoactivin fragments produced by ectodomain shedding induce MMP-3 expression via ERK pathway in mouse NIH-3T3 fibroblasts. FEBS letters 581:5743–5750

    Article  CAS  PubMed  Google Scholar 

  • Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002) Microglial activation‐mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81:1285–1297

    Article  CAS  PubMed  Google Scholar 

  • Griffin W, Stanley L, Ling C, White L, MacLeod V, Perrot L, White C, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in down syndrome and Alzheimer disease. Proc Natl Acad Sci 86:7611–7615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hinkerohe D, Smikalla D, Schoebel A, Haghikia A, Zoidl G, Haase CG, Schlegel U, Faustmann PM (2010) Dexamethasone prevents LPS-induced microglial activation and astroglial impairment in an experimental bacterial meningitis co-culture model. Brain research 1329:45–54

    Article  CAS  PubMed  Google Scholar 

  • Huang JJ, Ma WJ, Yokoyama S (2012) Expression and immunolocalization of Gpnmb, a glioma‐associated glycoprotein, in normal and inflamed central nervous systems of adult rats. Brain and behavior 2:85–96

    Article  PubMed Central  PubMed  Google Scholar 

  • Kuan CT, Wakiya K, Keir ST, Li J, Herndon JE, Pastan I, Bigner DD (2011) Affinity‐matured anti‐glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas. Int J Cancer 129:111–121

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu B, Hong J-S (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7

    Article  CAS  PubMed  Google Scholar 

  • Livak, K., Schmittgen, T. (2009) Analysis of relative gene expression data using real-time quantitative PCR and the 2 (−Delta Delta C (T) Method. Methods. 2001; 25 (4): 402–408. View this article via: PubMed CrossRef.

  • Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McDonald DR, Brunden KR, Landreth GE (1997) Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci 17:2284–2294

    CAS  PubMed  Google Scholar 

  • Minghetti L, Levi G (1998) Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 54:99–125

    Article  CAS  PubMed  Google Scholar 

  • Mun-Bryce S, Lukes A, Wallace J, Lukes-Marx M, Rosenberg GA (2002) Stromelysin-1 and gelatinase a are upregulated before TNF-α in LPS-stimulated neuroinflammation. Brain research 933:42–49

    Article  CAS  PubMed  Google Scholar 

  • Nuttall RK, Silva C, Hader W, Bar‐Or A, Patel KD, Edwards DR, Yong VW (2007) Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia. Glia 55:516–526

    Article  PubMed  Google Scholar 

  • Ogawa T, Nikawa T, Furochi H, Kosyoji M, Hirasaka K, Suzue N, Sairyo K, Nakano S, Yamaoka T, Itakura M (2005) Osteoactivin upregulates expression of MMP-3 and MMP-9 in fibroblasts infiltrated into denervated skeletal muscle in mice. Am J Physiol Cell Physiol 289:C697–C707

    Article  CAS  PubMed  Google Scholar 

  • Owen, T.A., Smock, S.L., Prakash, S., Pinder, L., Brees, D., Krull, D., Castleberry, T., Clancy, Y., Marks Jr, S.C., Safadi, F.F. (2003) Identification and characterization of the genes encoding human and mouse osteoactivin. Critical Reviews™ in Eukaryotic Gene Expression. 13.

  • Pahl MV, Vaziri ND, Yuan J, Adler SG (2010) Upregulation of monocyte/macrophage HGFIN (Gpnmb/Osteoactivin) expression in end-stage renal disease. Clin J Am Soc Nephrol 5:56–61

    Google Scholar 

  • Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201

    Article  PubMed  Google Scholar 

  • Punturee K, Wild CP, Vinitketkumneun U (2004) Thai medicinal plants modulate nitric oxide and tumor necrosis factor-α in J774. 2 mouse macrophages. J Ethnopharmacol 95:183–189

    Article  PubMed  Google Scholar 

  • Qin L, Block ML, Liu Y, Bienstock RJ, Pei Z, Zhang W, Wu X, Wilson B, Burka T, Hong J-S (2005) Microglial NADPH oxidase is a novel target for femtomolar neuroprotection against oxidative stress. FASEB J 19:550–557

    Article  CAS  PubMed  Google Scholar 

  • Rich JN, Shi Q, Hjelmeland M, Cummings TJ, Kuan C-T, Bigner DD, Counter CM, Wang X-F (2003) Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem 278:15951–15957

    Article  CAS  PubMed  Google Scholar 

  • Ripoll VM, Irvine KM, Ravasi T, Sweet MJ, Hume DA (2007) Gpnmb is induced in macrophages by IFN-γ and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. J Immunol 178:6557–6566

    Article  CAS  PubMed  Google Scholar 

  • Rose AA, Siegel PM (2010) Emerging therapeutic targets in breast cancer bone metastasis. Future Oncol 6:55–74

    Article  CAS  PubMed  Google Scholar 

  • Tanaka, H., Shimazawa, M., Kimura, M., Takata, M., Tsuruma, K., Yamada, M., Takahashi, H., Hozumi, I., Niwa, J.-i., Iguchi, Y. (2012) The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis. Scientific reports. 2.

  • Westermarck J, KÄHÄRI V-M (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13:781–792

    CAS  PubMed  Google Scholar 

  • Weterman MAJ, Ajubi N, van Dinter IMR, Degen WGJ, van Muijen GNP, Ruiter DJ, Bloemers HPJ (1995) nmb, a novel gene, is expressed in low鈥恗etastatic human melanoma cell lines and xenografts. Int J cancer 60:73–81

    Article  CAS  PubMed  Google Scholar 

  • Woo MS, Park JS, Choi IY, Kim WK, Kim HS (2008) Inhibition of MMP‐3 or‐9 suppresses lipopolysaccharide‐induced expression of proinflammatory cytokines and iNOS in microglia. J Neurochem 106:770–780

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

Financial support was provided by the National Natural Science Foundation of China (NSFC) (nos. 31270411 and J1210063) and the National Innovation Experiment Program for University Students (201310697024).

Disclosure Statement

The authors declare no competing financial interests. All authors have approved the final article.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jun Liu or Xin Xie.

Additional information

Fangyuan Shi, Shuangyan Duan, and Jihong Cui contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, F., Duan, S., Cui, J. et al. Induction of Matrix Metalloproteinase-3 (MMP-3) Expression in the Microglia by Lipopolysaccharide (LPS) via Upregulation of Glycoprotein Nonmetastatic Melanoma B (GPNMB) Expression. J Mol Neurosci 54, 234–242 (2014). https://doi.org/10.1007/s12031-014-0280-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-014-0280-0

Keywords

Navigation