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Transforming growth factor Beta1 induction of tissue inhibitor of metalloproteinases 3 in articular chondrocytes is mediated by reactive oxygen species.
Free Radic Biol Med. 2004 Jul 15; 37(2):196-207.FR

Abstract

Transforming growth factor beta1 (TGF-beta1) stimulates cartilage extracellular matrix synthesis but, in excess, evokes synovial inflammation, hyperplasia, and osteophyte formation in arthritic joints. TGF-beta1 induces tissue inhibitor of metalloproteinases 3 (TIMP-3), an inhibitor of cartilage-damaging matrix metalloproteianases and aggrecanases. We investigated the role of reactive oxygen species (ROS) in TIMP-3 induction by TGF-beta1. In primary human and bovine chondrocytes, ROS scavenger and antioxidant N-acetylcysteine (NAC) inhibited TGF-beta1-induced TIMP-3 mRNA and protein increases. Ebselen and ascorbate also reduced this induction. TGF-beta1 time-dependently induced ROS production that was suppressed by NAC. Hydrogen peroxide, a ROS, induced TIMP-3 RNA. The TIMP-3 increase induced by TGF-beta1 was partly Smad2-dependent. TGF-beta1-stimulated Smad2 phosphorylation was inhibited by NAC. Reduced glutathione and L-cysteine also blocked Smad2 and TIMP-3 induction by TGF-beta1, whereas a nonthiol, N-acetylalanine, did not. Smad2 was not activated by H2O2. Smad2 phosphorylation was independent, and TIMP-3 expression was dependent, on new protein synthesis. TGF-beta-stimulated ERK and JNK phosphorylation was also inhibited by NAC. However, inhibitory actions of NAC were not mediated by ERK activation. Thus, ROS mediate TGF-beta1-induced TIMP-3 gene expression. Blocking TGF-beta1-induced gene expression by modulating cellular redox status with thiols can be potentially beneficial for treating arthritic and other disorders caused by excessive TGF-beta1.

Authors+Show Affiliations

Department of Medicine, Notre-Dame Hospital, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15203191

Citation

Li, Wen Qing, et al. "Transforming Growth Factor Beta1 Induction of Tissue Inhibitor of Metalloproteinases 3 in Articular Chondrocytes Is Mediated By Reactive Oxygen Species." Free Radical Biology & Medicine, vol. 37, no. 2, 2004, pp. 196-207.
Li WQ, Qureshi HY, Liacini A, et al. Transforming growth factor Beta1 induction of tissue inhibitor of metalloproteinases 3 in articular chondrocytes is mediated by reactive oxygen species. Free Radic Biol Med. 2004;37(2):196-207.
Li, W. Q., Qureshi, H. Y., Liacini, A., Dehnade, F., & Zafarullah, M. (2004). Transforming growth factor Beta1 induction of tissue inhibitor of metalloproteinases 3 in articular chondrocytes is mediated by reactive oxygen species. Free Radical Biology & Medicine, 37(2), 196-207.
Li WQ, et al. Transforming Growth Factor Beta1 Induction of Tissue Inhibitor of Metalloproteinases 3 in Articular Chondrocytes Is Mediated By Reactive Oxygen Species. Free Radic Biol Med. 2004 Jul 15;37(2):196-207. PubMed PMID: 15203191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transforming growth factor Beta1 induction of tissue inhibitor of metalloproteinases 3 in articular chondrocytes is mediated by reactive oxygen species. AU - Li,Wen Qing, AU - Qureshi,Hamid Yaqoob, AU - Liacini,Abdelhamid, AU - Dehnade,Faramaze, AU - Zafarullah,Muhammad, PY - 2003/12/01/received PY - 2004/04/20/revised PY - 2004/04/22/accepted PY - 2004/6/19/pubmed PY - 2005/2/3/medline PY - 2004/6/19/entrez SP - 196 EP - 207 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 37 IS - 2 N2 - Transforming growth factor beta1 (TGF-beta1) stimulates cartilage extracellular matrix synthesis but, in excess, evokes synovial inflammation, hyperplasia, and osteophyte formation in arthritic joints. TGF-beta1 induces tissue inhibitor of metalloproteinases 3 (TIMP-3), an inhibitor of cartilage-damaging matrix metalloproteianases and aggrecanases. We investigated the role of reactive oxygen species (ROS) in TIMP-3 induction by TGF-beta1. In primary human and bovine chondrocytes, ROS scavenger and antioxidant N-acetylcysteine (NAC) inhibited TGF-beta1-induced TIMP-3 mRNA and protein increases. Ebselen and ascorbate also reduced this induction. TGF-beta1 time-dependently induced ROS production that was suppressed by NAC. Hydrogen peroxide, a ROS, induced TIMP-3 RNA. The TIMP-3 increase induced by TGF-beta1 was partly Smad2-dependent. TGF-beta1-stimulated Smad2 phosphorylation was inhibited by NAC. Reduced glutathione and L-cysteine also blocked Smad2 and TIMP-3 induction by TGF-beta1, whereas a nonthiol, N-acetylalanine, did not. Smad2 was not activated by H2O2. Smad2 phosphorylation was independent, and TIMP-3 expression was dependent, on new protein synthesis. TGF-beta-stimulated ERK and JNK phosphorylation was also inhibited by NAC. However, inhibitory actions of NAC were not mediated by ERK activation. Thus, ROS mediate TGF-beta1-induced TIMP-3 gene expression. Blocking TGF-beta1-induced gene expression by modulating cellular redox status with thiols can be potentially beneficial for treating arthritic and other disorders caused by excessive TGF-beta1. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/15203191/Transforming_growth_factor_Beta1_induction_of_tissue_inhibitor_of_metalloproteinases_3_in_articular_chondrocytes_is_mediated_by_reactive_oxygen_species_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891584904003491 DB - PRIME DP - Unbound Medicine ER -