Source:http://linkedlifedata.com/resource/pubmed/id/19494318
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
12
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| pubmed:dateCreated |
2009-6-4
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| pubmed:abstractText |
During osteoarthritis (OA) chondrocytes show deviant behavior resembling terminal differentiation of growth-plate chondrocytes, characterized by elevated MMP-13 expression. The latter is also a hallmark for OA. TGF-beta is generally thought to be a protective factor for cartilage, but it has also displayed deleterious effects in some studies. Recently, it was shown that besides signaling via the ALK5 (activin-like kinase 5) receptor, TGF-beta can also signal via ALK1, thereby activating Smad1/5/8 instead of Smad2/3. The Smad1/5/8 route can induce chondrocyte terminal differentiation. Murine chondrocytes stimulated with TGF-beta activated the ALK5 receptor/Smad2/3 route as well as the ALK1/Smad1/5/8 route. In cartilage of mouse models for aging and OA, ALK5 expression decreased much more than ALK1. Thus, the ALK1/ALK5 ratio increased, which was associated with changes in the respective downstream markers: an increased Id-1 (inhibitor of DNA binding-1)/PAI-1 (plasminogen activator inhibitor-1) ratio. Transfection of chondrocytes with adenovirus overexpressing constitutive active ALK1 increased MMP-13 expression, while small interfering RNA against ALK1 decreased MMP-13 expression to nondetectable levels. Adenovirus overexpressing constitutive active ALK5 transfection increased aggrecan expression, whereas small interfering RNA against ALK5 resulted in increased MMP-13 expression. Moreover, in human OA cartilage ALK1 was highly correlated with MMP-13 expression, whereas ALK5 correlated with aggrecan and collagen type II expression, important for healthy cartilage. Collectively, we show an age-related shift in ALK1/ALK5 ratio in murine cartilage and a strong correlation between ALK1 and MMP-13 expression in human cartilage. A change in balance between ALK5 and ALK1 receptors in chondrocytes caused changes in MMP-13 expression, thereby causing an OA-like phenotype. Our data suggest that dominant ALK1 signaling results in deviant chondrocyte behavior, thereby contributing to age-related cartilage destruction and OA.
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| pubmed:commentsCorrections | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
AIM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/ACVRL1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Activin Receptors, Type I,
http://linkedlifedata.com/resource/pubmed/chemical/Activin Receptors, Type II,
http://linkedlifedata.com/resource/pubmed/chemical/Acvrl1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Idb1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Inhibitor of Differentiation...,
http://linkedlifedata.com/resource/pubmed/chemical/MMP13 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 13,
http://linkedlifedata.com/resource/pubmed/chemical/Mmp13 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Plasminogen Activator Inhibitor 1,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Transforming Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/TGF-beta type I receptor
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
1550-6606
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:day |
15
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| pubmed:volume |
182
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
7937-45
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| pubmed:dateRevised |
2010-9-23
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| pubmed:meshHeading |
pubmed-meshheading:19494318-Activin Receptors, Type I,
pubmed-meshheading:19494318-Activin Receptors, Type II,
pubmed-meshheading:19494318-Aging,
pubmed-meshheading:19494318-Animals,
pubmed-meshheading:19494318-Cartilage,
pubmed-meshheading:19494318-Cells, Cultured,
pubmed-meshheading:19494318-Chondrocytes,
pubmed-meshheading:19494318-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:19494318-Humans,
pubmed-meshheading:19494318-Inhibitor of Differentiation Protein 1,
pubmed-meshheading:19494318-Male,
pubmed-meshheading:19494318-Matrix Metalloproteinase 13,
pubmed-meshheading:19494318-Mice,
pubmed-meshheading:19494318-Mice, Inbred C57BL,
pubmed-meshheading:19494318-Osteoarthritis,
pubmed-meshheading:19494318-Plasminogen Activator Inhibitor 1,
pubmed-meshheading:19494318-Protein-Serine-Threonine Kinases,
pubmed-meshheading:19494318-RNA, Messenger,
pubmed-meshheading:19494318-RNA Interference,
pubmed-meshheading:19494318-Receptors, Transforming Growth Factor beta,
pubmed-meshheading:19494318-Signal Transduction
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| pubmed:year |
2009
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| pubmed:articleTitle |
Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice.
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| pubmed:affiliation |
Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands. e.blaneydavidson@reuma.umcn.nl
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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