Abstract | INTRODUCTION: METHODS: Gene and protein expression of sPLA2-IIA, MMP-1, MMP-2, MMP-3, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were analyzed by real time PCR and ELISA respectively, in interleukin (IL)-1beta stimulated rheumatoid arthritis (RA) and osteoarthritis (OA) synovial fibroblasts cells treated with or without inhibitors of sPLA2 (PIP-18, LY315920) or MMPs ( MMP Inhibitor II). Phosphorylation status of mitogen-activated protein kinase (MAPK) proteins was examined by cell-based ELISA. The effect of PIP-18 was compared with that of celecoxib, methotrexate, infliximab and antiflamin-2 in Tg197 mice after ip administration (thrice weekly for 5 weeks) at two doses (10, 30 mg/kg), and histologic analysis of ankle joints. Serum sPLA2 and cytokines ( tumor necrosis factor ( TNF)alpha, IL-6) were measured by Escherichia coli (E coli) assay and ELISA, respectively. RESULTS: PIP-18 inhibited sPLA2-IIA production and enzymatic activity, and suppressed production of MMPs in IL-1beta-induced RA and OA SF cells. Treatment with PIP-18 blocked IL-1beta-induced p38 MAPK phosphorylation and resulted in attenuation of sPLA2-IIA and MMP mRNA transcription in RA SF cells. The disease modifying effect of PIP-18 was evidenced by significant abrogation of synovitis, cartilage degradation and bone erosion in hTNF Tg197 mice. CONCLUSIONS: Our results demonstrate the benefit that can be gained from using sPLA2 inhibitory peptide for RA treatment, and validate PIP-18 as a potential therapeutic in a clinically relevant animal model of human arthritis.
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Authors | Maung-Maung Thwin, Eleni Douni, Pachiappan Arjunan, George Kollias, Prem V Kumar, Ponnampalam Gopalakrishnakone |
Journal | Arthritis research & therapy
(Arthritis Res Ther)
Vol. 11
Issue 5
Pg. R138
( 2009)
ISSN: 1478-6362 [Electronic] England |
PMID | 19765281
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Interleukin-1beta
- Peptides
- Tumor Necrosis Factor-alpha
- Phospholipases A2, Secretory
- Matrix Metalloproteinases
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Topics |
- Animals
- Arthritis, Rheumatoid
(drug therapy, metabolism)
- Enzyme Inhibitors
(pharmacology)
- Enzyme-Linked Immunosorbent Assay
- Fibroblasts
(drug effects, metabolism)
- Gene Expression
- Humans
- Interleukin-1beta
(metabolism)
- Matrix Metalloproteinases
(biosynthesis, drug effects)
- Mice
- Mice, Transgenic
- Peptides
(pharmacology)
- Phospholipases A2, Secretory
(antagonists & inhibitors)
- Reverse Transcriptase Polymerase Chain Reaction
- Synovial Membrane
(cytology, drug effects, metabolism)
- Transcription, Genetic
- Tumor Necrosis Factor-alpha
(genetics)
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