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Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression.
Arthritis Rheum 2010; 62(10):3036-47AR

Abstract

OBJECTIVE

To determine whether intervertebral disc (IVD) cells express β-catenin and to assess the role of the WNT/β-catenin signaling pathway in cellular senescence and aggrecan synthesis.

METHODS

The expression of β-catenin messenger RNA (mRNA) and protein in rat IVD cells was assessed by using several real-time reverse transcription-polymerase chain reaction, Western blot, immunohistochemical, and immunofluorescence analyses. The effect of WNT/β-catenin on nucleus pulposus (NP) cells was examined by transfection experiments, an MTT assay, senescence-associated β-galactosidase staining, a cell cycle analysis, and a transforming growth factor (TGFβ)/bone morphogenetic protein (BMP) pathway-focused microarray analysis.

RESULTS

We found that β-catenin mRNA and protein were expressed in discs in vivo and that rat NP cells exhibited increased β-catenin mRNA and protein upon stimulation with lithium chloride, a known activator of WNT signaling. LiCl treatment inhibited the proliferation of NP cells in a time- and dose-dependent manner. In addition, there was an increased level of cellular senescence in LiCl-treated cells. Long-term treatment with LiCl induced cell cycle arrest and promoted subsequent apoptosis in NP cells. Activation of WNT/β-catenin signaling also regulated the expression of aggrecan. We also demonstrated that WNT/β-catenin signaling induced the expression of matrix metalloproteinases (MMPs) and TGFβ in NP cells.

CONCLUSION

The activation of WNT/β-catenin signaling promotes cellular senescence and may modulate MMP and TGFβ signaling in NP cells. We hypothesize that the activation of WNT/β-catenin signaling may lead to an increased breakdown of the matrix, thereby promoting IVD degeneration.

Authors+Show Affiliations

Tokai University School of Medicine, Isehara, Japan. a.hiyama@tokai-u.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20533544

Citation

Hiyama, Akihiko, et al. "Enhancement of Intervertebral Disc Cell Senescence By WNT/β-catenin Signaling-induced Matrix Metalloproteinase Expression." Arthritis and Rheumatism, vol. 62, no. 10, 2010, pp. 3036-47.
Hiyama A, Sakai D, Risbud MV, et al. Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum. 2010;62(10):3036-47.
Hiyama, A., Sakai, D., Risbud, M. V., Tanaka, M., Arai, F., Abe, K., & Mochida, J. (2010). Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. Arthritis and Rheumatism, 62(10), pp. 3036-47. doi:10.1002/art.27599.
Hiyama A, et al. Enhancement of Intervertebral Disc Cell Senescence By WNT/β-catenin Signaling-induced Matrix Metalloproteinase Expression. Arthritis Rheum. 2010;62(10):3036-47. PubMed PMID: 20533544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. AU - Hiyama,Akihiko, AU - Sakai,Daisuke, AU - Risbud,Makarand V, AU - Tanaka,Masahiro, AU - Arai,Fumiyuki, AU - Abe,Koichiro, AU - Mochida,Joji, PY - 2010/6/10/entrez PY - 2010/6/10/pubmed PY - 2010/12/14/medline SP - 3036 EP - 47 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 62 IS - 10 N2 - OBJECTIVE: To determine whether intervertebral disc (IVD) cells express β-catenin and to assess the role of the WNT/β-catenin signaling pathway in cellular senescence and aggrecan synthesis. METHODS: The expression of β-catenin messenger RNA (mRNA) and protein in rat IVD cells was assessed by using several real-time reverse transcription-polymerase chain reaction, Western blot, immunohistochemical, and immunofluorescence analyses. The effect of WNT/β-catenin on nucleus pulposus (NP) cells was examined by transfection experiments, an MTT assay, senescence-associated β-galactosidase staining, a cell cycle analysis, and a transforming growth factor (TGFβ)/bone morphogenetic protein (BMP) pathway-focused microarray analysis. RESULTS: We found that β-catenin mRNA and protein were expressed in discs in vivo and that rat NP cells exhibited increased β-catenin mRNA and protein upon stimulation with lithium chloride, a known activator of WNT signaling. LiCl treatment inhibited the proliferation of NP cells in a time- and dose-dependent manner. In addition, there was an increased level of cellular senescence in LiCl-treated cells. Long-term treatment with LiCl induced cell cycle arrest and promoted subsequent apoptosis in NP cells. Activation of WNT/β-catenin signaling also regulated the expression of aggrecan. We also demonstrated that WNT/β-catenin signaling induced the expression of matrix metalloproteinases (MMPs) and TGFβ in NP cells. CONCLUSION: The activation of WNT/β-catenin signaling promotes cellular senescence and may modulate MMP and TGFβ signaling in NP cells. We hypothesize that the activation of WNT/β-catenin signaling may lead to an increased breakdown of the matrix, thereby promoting IVD degeneration. SN - 1529-0131 UR - https://www.unboundmedicine.com/medline/citation/20533544/Enhancement_of_intervertebral_disc_cell_senescence_by_WNT/β_catenin_signaling_induced_matrix_metalloproteinase_expression_ L2 - https://doi.org/10.1002/art.27599 DB - PRIME DP - Unbound Medicine ER -