Skip to main content

Advertisement

SpringerLink
Log in

Acid-sensing ion channel 1a mediates acid-induced inhibition of matrix metabolism of rat articular chondrocytes via the MAPK signaling pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The acid-sensing ion channel 1a (ASIC1a), which is activated by extracellular acid, contributes to the pathogenesis of rheumatoid arthritis. However, it remains unclear whether ASIC1a mediates acid-induced matrix metabolism in rat articular chondrocytes via activation of the MAPK signaling pathway. In the current study, we found that extracellular acidification (pH 6.0) inhibited proliferation and induced apoptosis of articular chondrocytes in a dose-dependent manner, while the expression of phosphorylated ERK1/2 and P38 MAPK increased, but, this effect was blocked by the Ca2+ chelator BAPTA–AM and the ASIC1a-specific blocker PcTx-1. In addition, extracellular acidification increased the expression of c-fos, GAG, HYP, and TIM1/2. These effects were inhibited by the Ca2+ chelator BAPTA–AM, ERK1/2 inhibitor PD98059, and ASIC1a-specific blocker PcTx-1, but not the P38 MAPK inhibitor SB203580. Finally, extracellular acidification increased the expression of c-jun and MMP-2/9, and these effects were blocked by the Ca2+ chelator BAPTA–AM, P38 MAPK inhibitor SB203580, and ASIC1a-specific blocker PcTx-1, but not the ERK1/2 inhibitor PD98059. In conclusion, ASIC1a inhibits the expression of MMP-2/9, GAG, HYP, and TIMP-1/2 by the Ca2+-dependent P38 MAPK/c-jun and ERK/c-fos signaling pathways.

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

Access this article

Log in via an institution

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Lin YC, Liu YC, Huang YY, Lien CC (2010) High-density expression of Ca2+-permeable ASIC1a channels in NG2 glia of rat hippocampus. PLoS ONE. https://doi.org/10.1371/journal.pone.0012665

    Google Scholar 

  2. Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M (1997) A proton-gated cation channel involved in acid-sensing. Nature 386:173–177. https://doi.org/10.1038/386173a0

    Article  CAS  PubMed  Google Scholar 

  3. Wang YZ, Zeng WZ, Xiao X, Huang Y, Song XL, Yu Z, Tang D, Dong XP, Zhu MX, Xu TL (2013) Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death. Cell Death Differ 20:1359–1369. https://doi.org/10.1038/cdd.2013.90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Duan B, Wu LJ, Yu YQ, Ding Y, Jing L, Xu L, Chen J, Xu TL (2007) Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity. J Neurosci 27:11139–11148. https://doi.org/10.1523/JNEUROSCI.3364-07.2007

    Article  CAS  PubMed  Google Scholar 

  5. Yermolaieva O, Leonard AS, Schnizler MK, Abboud FM, Welsh MJ (2004) Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc Natl Acad Sci USA 101:6752–6757. https://doi.org/10.1073/pnas.0308636100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang YZ, Wang JJ, Huang Y, Liu F, Zeng WZ, Li Y, Xiong ZG, Zhu MX, Xu TL (2015) Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. Elife. https://doi.org/10.7554/eLife.05682

    Google Scholar 

  7. Sluka KA, Radhakrishnan R, Benson CJ, Eshcol JO, Price MP, Babinski K, Audette KM, Yeomans DC, Wilson SP (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain 129:102–112. https://doi.org/10.1016/j.pain.2006.09.038

    Article  PubMed  Google Scholar 

  8. Gong W, Kolker SJ, Usachev Y, Walder RY, Boyle DL, Firestein GS, Sluka KA (2014) Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium. Arthritis Res Ther 16:R121. https://doi.org/10.1186/ar4577

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kolker SJ, Walder RY, Usachev Y, Hillman J, Boyle DL, Firestein GS, Sluka KA (2010) Acid-sensing ion channel 3 expressed in type B synoviocytes and chondrocytes modulates hyaluronan expression and release. Ann Rheum Dis 69:903–909. https://doi.org/10.1136/ard.2009.117168

    Article  CAS  PubMed  Google Scholar 

  10. Rong C, Chen FH, Jiang S, Hu W, Wu FR, Chen TY, Yuan FL (2012) Inhibition of acid-sensing ion channels by amiloride protects rat articular chondrocytes from acid-induced apoptosis via a mitochondrial-mediated pathway. Cell Biol Int 36:635–641. https://doi.org/10.1042/CBI20110432

    Article  CAS  PubMed  Google Scholar 

  11. Salgado E, Maneiro JR (2014) New therapies for rheumatoid arthritis. Med Clin (Barc) 143:461–466. https://doi.org/10.1016/j.medcli.2013.11.011

    Article  Google Scholar 

  12. Verma RP, Hansch C (2007) Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem 15:2223–2268. https://doi.org/10.1016/j.bmc.2007.01.011

    Article  CAS  PubMed  Google Scholar 

  13. Wu MH, Urban JP, Cui ZF, Cui Z, Xu X (2007) Effect of extracellular ph on matrix synthesis by chondrocytes in 3D agarose gel. Biotechnol Prog 23:430–434. https://doi.org/10.1021/bp060024v

    Article  CAS  PubMed  Google Scholar 

  14. Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405. https://doi.org/10.1016/j.bbadis.2009.12.009

    Article  CAS  PubMed  Google Scholar 

  15. Osaki LH, Gama P (2013) MAPKs and signal transduction in the control of gastrointestinal epithelial cell proliferation and differentiation. Int J Mol Sci 14:10143–10161. https://doi.org/10.3390/ijms140510143

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ross EA, Naylor AJ, O’Neil JD, Crowley T, Ridley ML, Crowe J, Smallie T, Tang TJ, Turner JD, Norling LV, Dominguez S, Perlman H, Verrills NM, Kollias G, Vitek MP, Filer A, Buckley CD, Dean JL, Clark AR (2017) Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression. Ann Rheum Dis 76:612–619. https://doi.org/10.1136/annrheumdis-2016-209424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. de Launay D, van de Sande MG, de Hair MJ, Grabiec AM, van de Sande GP, Lehmann KA, Wijbrandts CA, van Baarsen LG, Gerlag DM, Tak PP, Reedquist KA (2012) Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets. Ann Rheum Dis 71:415–423. https://doi.org/10.1136/ard.2010.143529

    Article  PubMed  Google Scholar 

  18. Criado G, Risco A, Alsina-Beauchamp D, Perez-Lorenzo MJ, Escos A, Cuenda A (2014) Alternative p38 MAPKs are essential for collagen-induced arthritis. Arthritis Rheumatol 66:1208–1217. https://doi.org/10.1002/art.38327

    Article  CAS  PubMed  Google Scholar 

  19. Yuan FL, Chen FH, Lu WG, Li X, Wu FR, Li JP, Li CW, Wang Y, Zhang TY, Hu W (2010) Acid-sensing ion channel 1a mediates acid-induced increases in intracellular calcium in rat articular chondrocytes. Mol Cell Biochem 340:153–159. https://doi.org/10.1007/s11010-010-0412-y

    Article  CAS  PubMed  Google Scholar 

  20. Ponce A (2006) Expression of voltage dependent potassium currents in freshly dissociated rat articular chondrocytes. Cell Physiol Biochem 18:35–46. https://doi.org/10.1159/000095134

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Y, Zhang T, Wu C, Xia Q, Xu D (2017) ASIC1a mediates the drug resistance of human hepatocellular carcinoma via the Ca2+/PI3-kinase/AKT signaling pathway. Lab Investig 97:53–69. https://doi.org/10.1038/labinvest.2016.127

    Article  CAS  PubMed  Google Scholar 

  22. Honda K, Ohno S, Tanimoto K, Ijuin C, Tanaka N, Doi T, Kato Y, Tanne K (2000) The effects of high magnitude cyclic tensile load on cartilage matrix metabolism in cultured chondrocytes. Eur J Cell Biol 79:601–609. https://doi.org/10.1078/0171-9335-00089

    Article  CAS  PubMed  Google Scholar 

  23. Razaq S, Wilkins RJ, Urban JP (2003) The effect of extracellular pH on matrix turnover by cells of the bovine nucleus pulposus. Eur Spine J 12:341–349. https://doi.org/10.1007/s00586-003-0582-3

    Article  PubMed  PubMed Central  Google Scholar 

  24. Herrera Y, Katnik C, Rodriguez JD, Hall AA, Willing A, Pennypacker KR, Cuevas J (2008) sigma-1 receptor modulation of acid-sensing ion channel a (ASIC1a) and ASIC1a-induced Ca2+ influx in rat cortical neurons. J Pharmacol Exp Ther 327:491–502. https://doi.org/10.1124/jpet.108.143974

    Article  CAS  PubMed  Google Scholar 

  25. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529. https://doi.org/10.1038/nrm1155

    Article  CAS  PubMed  Google Scholar 

  26. Yi M, Zhao Q, Tang J, Wang C (2011) A theoretical modeling for frequency modulation of Ca(2+) signal on activation of MAPK cascade. Biophys Chem 157:33–42. https://doi.org/10.1016/j.bpc.2011.04.007

    Article  CAS  PubMed  Google Scholar 

  27. Matijevic Glavan T, Cipak Gasparovic A, Verillaud B, Busson P, Pavelic J (2017) Toll-like receptor 3 stimulation triggers metabolic reprogramming in pharyngeal cancer cell line through Myc, MAPK, and HIF. Mol Carcinog 56:1214–1226. https://doi.org/10.1002/mc.22584

    Article  CAS  PubMed  Google Scholar 

  28. Chen Z, Shen H, Sun C, Yin L, Tang F, Zheng P, Liu Y, Brink R, Rui L (2015) Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity. Am J Physiol Endocrinol Metab 308:E460–E469. https://doi.org/10.1152/ajpendo.00470.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ratnikov BI, Scott DA, Osterman AL, Smith JW, Ronai ZA (2017) Metabolic rewiring in melanoma. Oncogene 36:147–157. https://doi.org/10.1038/onc.2016.198

    Article  CAS  PubMed  Google Scholar 

  30. Roth Flach RJ, Bennett AM (2010) Mitogen-activated protein kinase phosphatase-1 - a potential therapeutic target in metabolic disease. Expert Opin Ther Targets 14:1323–1332. https://doi.org/10.1517/14728222.2010.528395

    Article  PubMed  Google Scholar 

  31. Liu WH, Chang LS (2010) Caffeine induces matrix metalloproteinase-2 (MMP-2) and MMP-9 down-regulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-fos pathway and activation of p38 MAPK/c-jun pathway. J Cell Physiol 224:775–785. https://doi.org/10.1002/jcp.22180

    Article  CAS  PubMed  Google Scholar 

  32. Ding L, Heying E, Nicholson N, Stroud NJ, Homandberg GA, Buckwalter JA, Guo D, Martin JA (2010) Mechanical impact induces cartilage degradation via mitogen activated protein kinases. Osteoarthr Cartil 18:1509–1517. https://doi.org/10.1016/j.joca.2010.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Loeser RF, Erickson EA, Long DL (2008) Mitogen-activated protein kinases as therapeutic targets in osteoarthritis. Curr Opin Rheumatol 20:581–586. https://doi.org/10.1097/BOR.0b013e3283090463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sondergaard BC, Schultz N, Madsen SH, Bay-Jensen AC, Kassem M, Karsdal MA (2010) MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation–divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation. Osteoarthr Cartil 18:279–288. https://doi.org/10.1016/j.joca.2009.11.005

    Article  PubMed  Google Scholar 

  35. Yang Q, Chen C, Wu S, Zhang Y, Mao X, Wang W (2010) Advanced glycation end products downregulates peroxisome proliferator-activated receptor gamma expression in cultured rabbit chondrocyte through MAPK pathway. Eur J Pharmacol 649:108–114. https://doi.org/10.1016/j.ejphar.2010.09.025

    Article  CAS  PubMed  Google Scholar 

  36. Brandl N, Zemann A, Kaupe I, Marlovits S, Huettinger P, Goldenberg H, Huettinger M (2010) Signal transduction and metabolism in chondrocytes is modulated by lactoferrin. Osteoarthr Cartil 18:117–125. https://doi.org/10.1016/j.joca.2009.08.012

    Article  CAS  PubMed  Google Scholar 

  37. Rockel JS, Bernier SM, Leask A (2009) Egr-1 inhibits the expression of extracellular matrix genes in chondrocytes by TNFalpha-induced MEK/ERK signalling. Arthritis Res Ther 11:R8. https://doi.org/10.1186/ar2595

    Article  PubMed  PubMed Central  Google Scholar 

  38. Chowdhury TT, Salter DM, Bader DL, Lee DA (2008) Signal transduction pathways involving p38 MAPK, JNK, NFkappaB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1beta and dynamic compression. Inflamm Res 57:306–313. https://doi.org/10.1007/s00011-007-7126-y

    Article  CAS  PubMed  Google Scholar 

  39. Eilam Y, Beit-Or A, Nevo Z (1985) Decrease in cytosolic free Ca2+ and enhanced proteoglycan synthesis induced by cartilage derived growth factors in cultured chondrocytes. Biochem Biophys Res Commun 132:770–779

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This project was supported by Anhui Provincial Natural Science Foundation (No. 1408085MH151) and Specialized Research Fund for the Doctoral Program of Higher Education (No. 20133420120002).

Author information

Authors and Affiliations

  1. Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China

    Cheng Sun, Shimin Wang & Wei Hu

Authors
  1. Cheng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shimin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Hu.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, C., Wang, S. & Hu, W. Acid-sensing ion channel 1a mediates acid-induced inhibition of matrix metabolism of rat articular chondrocytes via the MAPK signaling pathway. Mol Cell Biochem 443, 81–91 (2018). https://doi.org/10.1007/s11010-017-3212-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3212-9

Keywords

Search

Navigation