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Peroxisome proliferator--activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes.
Arthritis Rheum. 2001 Mar; 44(3):595-607.AR

Abstract

OBJECTIVE

To determine the effects of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on interleukin-1 (IL-1) induction of nitric oxide (NO) and matrix metalloproteinase 13 (MMP-13) in human chondrocytes.

METHODS

PPARgamma expression and synthesis in human chondrocytes were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. Chondrocytes were cultured with IL-1beta, tumor necrosis factor alpha (TNFalpha), and IL-17 in the presence or absence of PPARgamma agonists, and NO and MMP-13 synthesis and expression levels were measured. Transient transfection experiments were performed with the 7-kb inducible NO synthase (iNOS) and 1.6-kb MMP-13 human promoters, as well as with the PPARgamma expression vector and the activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) reporter constructs.

RESULTS

RT-PCR and immunohistochemical analysis revealed that human chondrocytes expressed and produced PPARgamma. Treatment of chondrocytes with PPARgamma ligands BRL 49653 and 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2), but not with PPARalpha ligand Wy 14643, decreased IL-1beta-induced NO and MMP-13 production in a dose-dependent manner. In addition, both iNOS and MMP-13 messenger RNA were inhibited in the presence of 15d-PGJ2. The inhibitory effect of PPARgamma activation was not restricted to IL-1beta, since TNFalpha- and IL-17-induced NO and MMP-13 production were also inhibited by 15d-PGJ2. In transient transfection experiments, we showed that a constitutively active form of mitogen-activated protein kinase kinase kinase 1 (AMEKK-1) induced the MMP-13 and iNOS human promoter activity. This process was reduced by 15d-PGJ2 and further inhibited by cotransfection with a PPARgamma expression vector. Similarly, in a PPARgamma-dependent manner, 15d-PGJ2 inhibited deltaMEKK-1-induced AP-1- and NF-kappaB-luciferase reporter plasmid activation.

CONCLUSION

The findings of this study demonstrate that PPARgamma agonists inhibit IL-1beta induction of both NO and MMP-13 in human chondrocytes. The inhibition occurs at least at the transcriptional level through a PPARgamma-dependent pathway, probably by interfering with the activation of AP-1 and NF-kappaB.

Authors+Show Affiliations

H pital Notre-Dame, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11263774

Citation

Fahmi, H, et al. "Peroxisome Proliferator--activated Receptor Gamma Activators Inhibit Interleukin-1beta-induced Nitric Oxide and Matrix Metalloproteinase 13 Production in Human Chondrocytes." Arthritis and Rheumatism, vol. 44, no. 3, 2001, pp. 595-607.
Fahmi H, Di Battista JA, Pelletier JP, et al. Peroxisome proliferator--activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis Rheum. 2001;44(3):595-607.
Fahmi, H., Di Battista, J. A., Pelletier, J. P., Mineau, F., Ranger, P., & Martel-Pelletier, J. (2001). Peroxisome proliferator--activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis and Rheumatism, 44(3), 595-607.
Fahmi H, et al. Peroxisome Proliferator--activated Receptor Gamma Activators Inhibit Interleukin-1beta-induced Nitric Oxide and Matrix Metalloproteinase 13 Production in Human Chondrocytes. Arthritis Rheum. 2001;44(3):595-607. PubMed PMID: 11263774.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peroxisome proliferator--activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. AU - Fahmi,H, AU - Di Battista,J A, AU - Pelletier,J P, AU - Mineau,F, AU - Ranger,P, AU - Martel-Pelletier,J, PY - 2001/3/27/pubmed PY - 2001/5/5/medline PY - 2001/3/27/entrez SP - 595 EP - 607 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 44 IS - 3 N2 - OBJECTIVE: To determine the effects of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on interleukin-1 (IL-1) induction of nitric oxide (NO) and matrix metalloproteinase 13 (MMP-13) in human chondrocytes. METHODS: PPARgamma expression and synthesis in human chondrocytes were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. Chondrocytes were cultured with IL-1beta, tumor necrosis factor alpha (TNFalpha), and IL-17 in the presence or absence of PPARgamma agonists, and NO and MMP-13 synthesis and expression levels were measured. Transient transfection experiments were performed with the 7-kb inducible NO synthase (iNOS) and 1.6-kb MMP-13 human promoters, as well as with the PPARgamma expression vector and the activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) reporter constructs. RESULTS: RT-PCR and immunohistochemical analysis revealed that human chondrocytes expressed and produced PPARgamma. Treatment of chondrocytes with PPARgamma ligands BRL 49653 and 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2), but not with PPARalpha ligand Wy 14643, decreased IL-1beta-induced NO and MMP-13 production in a dose-dependent manner. In addition, both iNOS and MMP-13 messenger RNA were inhibited in the presence of 15d-PGJ2. The inhibitory effect of PPARgamma activation was not restricted to IL-1beta, since TNFalpha- and IL-17-induced NO and MMP-13 production were also inhibited by 15d-PGJ2. In transient transfection experiments, we showed that a constitutively active form of mitogen-activated protein kinase kinase kinase 1 (AMEKK-1) induced the MMP-13 and iNOS human promoter activity. This process was reduced by 15d-PGJ2 and further inhibited by cotransfection with a PPARgamma expression vector. Similarly, in a PPARgamma-dependent manner, 15d-PGJ2 inhibited deltaMEKK-1-induced AP-1- and NF-kappaB-luciferase reporter plasmid activation. CONCLUSION: The findings of this study demonstrate that PPARgamma agonists inhibit IL-1beta induction of both NO and MMP-13 in human chondrocytes. The inhibition occurs at least at the transcriptional level through a PPARgamma-dependent pathway, probably by interfering with the activation of AP-1 and NF-kappaB. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/11263774/Peroxisome_proliferator__activated_receptor_gamma_activators_inhibit_interleukin_1beta_induced_nitric_oxide_and_matrix_metalloproteinase_13_production_in_human_chondrocytes_ L2 - https://doi.org/10.1002/1529-0131(200103)44:3<595::AID-ANR108>3.0.CO;2-8 DB - PRIME DP - Unbound Medicine ER -