Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction
Pro-inflammatory cytokines induce meniscal matrix degradation and inhibition of endogenous repair mechanisms, but the pathogenic mechanisms behind this are mostly unknown. Therefore, we investigated details of interleukin-1 (IL-1α)-induced aggrecan turnover in mature meniscal tissue explants. Fibro-...
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| Format: | Article |
| Language: | en_US |
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Springer-Verlag
2012
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| Online Access: | http://hdl.handle.net/1721.1/69547 https://orcid.org/0000-0002-4942-3456 |
| _version_ | 1826214153771024384 |
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| author | Lemke, Angelika K. Sandy, John D. Voigt, Henning Dreier, Rita Lee, Jennifer H. Grodzinsky, Alan J. Mentlein, Rolf Fay, Jakob Schunke, Michael Kurz, Bodo |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Lemke, Angelika K. Sandy, John D. Voigt, Henning Dreier, Rita Lee, Jennifer H. Grodzinsky, Alan J. Mentlein, Rolf Fay, Jakob Schunke, Michael Kurz, Bodo |
| author_sort | Lemke, Angelika K. |
| collection | MIT |
| description | Pro-inflammatory cytokines induce meniscal matrix degradation and inhibition of endogenous repair mechanisms, but the pathogenic mechanisms behind this are mostly unknown. Therefore, we investigated details of interleukin-1 (IL-1α)-induced aggrecan turnover in mature meniscal tissue explants. Fibro-cartilagenous disks (3 mm diameter × 1 mm thickness) were isolated from the central, weight-bearing region of menisci from 2-year-old cattle. After 3 or 6 days of IL-1α-treatment, GAG loss (DMMB assay), biosynthetic activity ([35SO4]-sulfate and [3H]-proline incorporation), gene expression (quantitative RT-PCR) and the abundance (zymography, Western blot) of matrix-degrading enzymes and specific aggrecan products were determined. Meniscal fibrocartilage had a 4-fold lower GAG content (per wet weight) than adjacent articular cartilage, and expressed MMPs-1, -2, -3 and ADAMTS4 constitutively, whereas ADAMTS5 m-RNA was essentially undetectable. Significant IL-1 effects were a decrease in biosynthetic activity, an increase in GAG release and in the expression/abundance of MMP-2, MMP-3 and ADAMTS4. Fresh tissue contained aggrecan core protein products similar to those previously described for bovine articular cartilage of this age. IL-1 induced the release of aggrecanase-generated CS-substituted products including both high (>250 kDa) and low molecular weight (about 75 kDa) species. TIMP-3 (but not TIMP-1 and -2 or a broad spectrum MMP inhibitor) inhibited IL-1-dependent GAG loss. In addition, IL-1 induced the release of preformed pools of three known G1-bearing products. We conclude that aggrecanases are responsible for IL-1-stimulated GAG release from meniscal explants, and that IL-1 also stimulates release of G1-bearing products, by a process possibly involving hyaluronan fragmentation. |
| first_indexed | 2024-09-23T16:00:40Z |
| format | Article |
| id | mit-1721.1/69547 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:00:40Z |
| publishDate | 2012 |
| publisher | Springer-Verlag |
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| spelling | mit-1721.1/695472022-09-29T17:39:39Z Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction Interleukin-1α treatment of meniscal explants stimulates the production and release of aggrecanase-generated, GAG-substituted aggrecan products and also the release of pre-formed, aggrecanase-generated G1 and m-calpain-generated G1-G2 Lemke, Angelika K. Sandy, John D. Voigt, Henning Dreier, Rita Lee, Jennifer H. Grodzinsky, Alan J. Mentlein, Rolf Fay, Jakob Schunke, Michael Kurz, Bodo Massachusetts Institute of Technology. Department of Biological Engineering Grodzinsky, Alan J. Grodzinsky, Alan J. Pro-inflammatory cytokines induce meniscal matrix degradation and inhibition of endogenous repair mechanisms, but the pathogenic mechanisms behind this are mostly unknown. Therefore, we investigated details of interleukin-1 (IL-1α)-induced aggrecan turnover in mature meniscal tissue explants. Fibro-cartilagenous disks (3 mm diameter × 1 mm thickness) were isolated from the central, weight-bearing region of menisci from 2-year-old cattle. After 3 or 6 days of IL-1α-treatment, GAG loss (DMMB assay), biosynthetic activity ([35SO4]-sulfate and [3H]-proline incorporation), gene expression (quantitative RT-PCR) and the abundance (zymography, Western blot) of matrix-degrading enzymes and specific aggrecan products were determined. Meniscal fibrocartilage had a 4-fold lower GAG content (per wet weight) than adjacent articular cartilage, and expressed MMPs-1, -2, -3 and ADAMTS4 constitutively, whereas ADAMTS5 m-RNA was essentially undetectable. Significant IL-1 effects were a decrease in biosynthetic activity, an increase in GAG release and in the expression/abundance of MMP-2, MMP-3 and ADAMTS4. Fresh tissue contained aggrecan core protein products similar to those previously described for bovine articular cartilage of this age. IL-1 induced the release of aggrecanase-generated CS-substituted products including both high (>250 kDa) and low molecular weight (about 75 kDa) species. TIMP-3 (but not TIMP-1 and -2 or a broad spectrum MMP inhibitor) inhibited IL-1-dependent GAG loss. In addition, IL-1 induced the release of preformed pools of three known G1-bearing products. We conclude that aggrecanases are responsible for IL-1-stimulated GAG release from meniscal explants, and that IL-1 also stimulates release of G1-bearing products, by a process possibly involving hyaluronan fragmentation. Endo-Stiftung 2012-03-01T18:49:03Z 2012-03-01T18:49:03Z 2010-03 2009-07 Article http://purl.org/eprint/type/JournalArticle 0302-766X 1432-0878 http://hdl.handle.net/1721.1/69547 Lemke, Angelika K. et al. “Interleukin-1α Treatment of Meniscal Explants Stimulates the Production and Release of Aggrecanase-generated, GAG-substituted Aggrecan Products and Also the Release of Pre-formed, Aggrecanase-generated G1 and M-calpain-generated G1-G2.” Cell and Tissue Research 340.1 (2010): 179–188. https://orcid.org/0000-0002-4942-3456 en_US http://dx.doi.org/10.1007/s00441-010-0941-4 Cell Tissue Research Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Springer-Verlag Prof. Grodzinsky via Howard Silver |
| spellingShingle | Lemke, Angelika K. Sandy, John D. Voigt, Henning Dreier, Rita Lee, Jennifer H. Grodzinsky, Alan J. Mentlein, Rolf Fay, Jakob Schunke, Michael Kurz, Bodo Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction |
| title | Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction |
| title_full | Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction |
| title_fullStr | Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction |
| title_full_unstemmed | Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction |
| title_short | Interleukin-1α induces ADAMTS-mediated aggrecanolysis in the bovine meniscus: evidence for a primary role of ADAMTS-4 in meniscus destruction |
| title_sort | interleukin 1α induces adamts mediated aggrecanolysis in the bovine meniscus evidence for a primary role of adamts 4 in meniscus destruction |
| url | http://hdl.handle.net/1721.1/69547 https://orcid.org/0000-0002-4942-3456 |
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