Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis
Abstract
Objective: To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis. Methods: Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB. Interaction between CREB and the Cyr61 promoter was evaluated by electrophoretic mobility shift assay and chromatin immunoprecipitation. CCL2 expression was examined by Northern blotting and enzyme‐linked immunosorbent assay. In rats with collagen‐induced arthritis (CIA), osteoblastic expression of Cyr61 was examined by immunohistochemistry, and disease progression was assessed by clinical, radiographic, and histologic examination. Results: In primary human osteoblasts and U2OS cells, Cyr61 expression stimulated by tumor necrosis factor α, interleukin‐1β (IL‐1β), oncostatin M (OSM), and other IL‐6–family cytokines was suppressed by simvastatin. In U2OS cells, simvastatin inhibited OSM‐induced CREB phosphorylation and CREB–DNA binding. Knockdown of CREB by short hairpin RNA reduced Cyr61 synthesis. OSM‐induced Cyr61 promoter activation was dependent on CRE–CREB interaction and inhibited by simvastatin. Cyr61 enhanced CCL2 expression by U2OS cells. Intraarticular injection of simvastatin inhibited CIA progression and diminished the number of Cyr61+ osteoblasts and infiltrating macrophages. Conclusion: Simvastatin inhibited cytokine‐stimulated Cyr61 expression in osteoblastic cells and suppressed disease progression and osteoblastic expression of Cyr61 in inflammatory arthritis. This finding indicates that simvastatin may have potential as a therapeutic agent for inflammatory arthritis.
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Inhibition of CCN1 expression correlates with suppression of inflammatory arthritis.
“CCN1 is highly expressed in collagen-induced arthritis in rodents, and inhibition of CCN1 expression correlates with suppression of inflammatory arthritis [134].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [134]
CCN1 is highly expressed in collagen-induced arthritis in rodents.
“CCN1 is highly expressed in collagen-induced arthritis in rodents, and inhibition of CCN1 expression correlates with suppression of inflammatory arthritis [134].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [134]
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References 42 · Cited by 30
- Authors
- Kok, S., Hou, K., Hong, C., Wang, J., Liang, P., Chang, C., Hsiao, M., Yang, H., Lai, E. H., & Lin, S.
- Affiliations
- National Taiwan University (TW)
- National Taiwan University Hospital (TW)
- Academia Sinica (TW)
- ORCID
- Venue
- Arthritis & Rheumatism
- Publisher
- Wiley
- Published
- 2011-03-30
- Volume
- 63
- Issue
- 4
- Pages
- 1010-1020
- ISSN
- 0004-3591 (ISSN-L)
- 1529-0131
- OpenAlex
- W2001565507
- Cited by
- 30
- References
- 42
- Citations by year
- 2025: 1 · 2023: 3 · 2021: 1 · 2020: 2 · 2019: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 6 · 2013: 1 · 2012: 4
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arthritis & Rheumatism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- simvastatin, CYR61, osteoblasts, inflammatory arthritis, collagen-induced arthritis, CREB phosphorylation, inflammatory cytokines, oncostatin M, IL-1β, TNF-α, MCP-1, macrophage infiltration, statins
- MeSH terms
- Animals, Anticholesteremic Agents, Arthritis, Experimental, Cells, Cultured, Disease Models, Animal, Humans, Injections, Intra-Articular, Male, Osteoblasts, Cytokines, Treatment Outcome, Rats, Sprague-Dawley, Cyclic AMP Response Element-Binding Protein, Disease Progression, Chemokine CCL2, Simvastatin, Cell Line, Tumor, Rats, Cysteine-Rich Protein 61
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