Document Detail


IGF-1 regulation of type II collagen and MMP-13 expression in rat endplate chondrocytes via distinct signaling pathways.
MedLine Citation:
PMID:  18595745     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Abnormal maturation and ossification of the endplate chondrocytes play a central role in the pathogenesis of degenerative disorders of the cervical spine. It is widely held that insulin like growth factor-1 (IGF-1) stimulates chondrocyte proliferation and inhibits chondrocyte terminal differentiation both in vitro and in vivo. However, the mechanism underlying such regulation is not fully understood. The present study aimed to determine the role of IGF-1 on the mRNA expression of collagen type II, alpha 1 (Col2a1) and matrix metallopeptidase 13 (MMP-13) in rat endplate chondrocytes. The possible pathways that transduce IGF-1 effects such as phosphatidylinositol-3 (PI-3)-kinase (PI3K) and mitogen activated protein kinase (MAPK) were also investigated in these cells. METHODS: Cultured endplate chondrocytes harvested from rat cervical spines were treated with IGF-1 (100ng/ml), and the changes in Col2a1 and MMP-13 mRNA were monitored with real-time polymerase chain reaction (PCR). MMP-13 activity was also assayed. Activation of signaling proteins was evaluated by western blot analysis. Cells were also treated with pharmacological agents that block PI3K and MAPK signaling pathways. RESULTS: IGF-1 increased Col2a1 mRNA expression in rat endplate chondrocytes in a time- and dose-dependent manner. IGF-1 treatment resulted in a fourfold increase of Col2a1 mRNA with the effect maximizing at 24h. In contrast, IGF-1 treatment for 24h caused a roughly 50% reduction in MMP-13 mRNA. Similar effects were seen on the protein levels of type II collagen (col2) and MMP-13. Consistent with these results, IGF-1 also repressed MMP-13 activity. IGF-1 activated both the PI3K and the extracellular signal-regulated kinase (ERK) pathways as evidenced by phosphorylation of either Akt or ERK1/2 (respectively). The PI3K inhibitor Wartmannin significantly inhibited the IGF-1 effect on Col2a1 mRNA expression but did not affect IGF-1-induced repression of MMP-13 expression. In contrast, the ERK/MAPK inhibitor PD98059 significantly inhibited the effect of IGF-1 on MMP-13 mRNA repression and enhanced IGF-1-induced Col2a1 mRNA expression. CONCLUSIONS: In rat endplate chondrocytes the PI3K pathway mainly transduces IGF-1 effect on col2 expression while the ERK pathway mediates IGF-1 effect on MMP-13 expression.
Authors:
M Zhang; Q Zhou; Q-Q Liang; C-G Li; J D Holz; D Tang; T-J Sheu; T-F Li; Q Shi; Y-J Wang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-01
Journal Detail:
Title:  Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society     Volume:  17     ISSN:  1522-9653     ISO Abbreviation:  Osteoarthr. Cartil.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-16     Completed Date:  2009-05-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9305697     Medline TA:  Osteoarthritis Cartilage     Country:  England    
Other Details:
Languages:  eng     Pagination:  100-6     Citation Subset:  IM    
Affiliation:
Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Cervical Vertebrae / drug effects*,  metabolism
Chondrocytes / drug effects*,  metabolism
Collagen Type II / biosynthesis*,  genetics
Dose-Response Relationship, Drug
Down-Regulation / drug effects
Gene Expression Regulation, Enzymologic / drug effects
Insulin-Like Growth Factor I / pharmacology*
MAP Kinase Signaling System / drug effects*,  physiology
Matrix Metalloproteinase 13 / biosynthesis*
RNA, Messenger / genetics
Rats
Rats, Sprague-Dawley
Transcription, Genetic
Up-Regulation / drug effects
Chemical
Reg. No./Substance:
0/COL2A1 protein, rat; 0/Collagen Type II; 0/RNA, Messenger; 67763-96-6/Insulin-Like Growth Factor I; EC 3.4.24.-/Matrix Metalloproteinase 13

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