PGE2 signal through EP2 promotes the growth of articular chondrocytes

Tomoki Aoyama, Bojian Liang, Takeshi Okamoto, Takashi Matsusaki, Koichi Nishijo, Tatsuya Ishibe, Ko Yasura, Satoshi Nagayama, Tomitaka Nakayama, Takashi Nakamura, Junya Toguchida

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

EP2 was identified as the major PGE2 receptor expressed in articular cartilage. An EP2 agonist increased intracellular cAMP in articular chondrocytes, stimulating DNA synthesis in both monolayer and 3D cultures. Hence, the EP2 agonist may be a potent therapeutic agent for degenerative cartilage diseases. Introduction: Prostaglandin E2 (PGE2) exhibits pleiotropic effects in various types of tissue through four types of receptors, EP1-4. We examined the expression of EPs and effects of agonists for each EP on articular chondrocytes. Materials and Methods: The expression of each EP in articular chondrocytes was examined by immunohistochemistry and RT-PCR. A chondrocyte cell line, MMA2, was established from articular cartilage of p53-/- mice and used to analyze the effects of agonists for each EP. A search for molecules downstream of the PGE2 signal through the EP2 agonist was made by cDNA microarray analysis. The growth-promoting effect of the EP2 agonist on chondrocytes surrounded by cartilage matrix was examined in an organ culture of rat femora. Results and Conclusion: EP2 was identified as the major EP expressed in articular cartilage. Treatment of MMA2 cells with specific agonists for each EP showed that only the EP2 agonist significantly increased intracellular cAMP levels in a dose-dependent manner. Gene expression profiling of MMA2 revealed a set of genes upregulated by the EP2 agonist, including several growth-promoting and apoptosis-protecting genes such as the cyclin D1, fibronectin, integrin α5, AP2α, and 14-3-3γ genes. The upregulation of these genes by the EP2 agonist was confirmed in human articular chondrocytes by quantitative mRNA analysis. On treatment with the EP2 agonist, human articular chondrocytes showed an increase in the incorporation of 5-bromo-2-deoxyuracil (BrdU), and the organ culture of rat femora showed an increase of proliferating cell nuclear antigen (PCNA) staining in articular chondrocytes surrounded by cartilage matrix, suggesting growth-promoting effects of the PGE2 signal through EP2 in articular cartilage. These results suggested that the PGE2 signal through EP2 enhances the growth of articular chondrocytes, and the EP2 agonist is a candidate for a new therapeutic compound for the treatment of degenerative cartilage diseases.

Original languageEnglish
Pages (from-to)377-389
Number of pages13
JournalJournal of Bone and Mineral Research
Volume20
Issue number3
DOIs
Publication statusPublished - Mar 2005
Externally publishedYes

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Chondrocytes
Dinoprostone
Joints
Growth
Articular Cartilage
Cartilage Diseases
Organ Culture Techniques
Femur
Genes
Cartilage
Prostaglandin Receptors
Cyclin D1
Proliferating Cell Nuclear Antigen
Gene Expression Profiling
Therapeutics
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Fibronectins
Integrins
Up-Regulation

Keywords

  • Articular cartilage
  • Chondrocyte
  • EP2
  • Microarray
  • Prostaglandin E2

ASJC Scopus subject areas

  • Surgery

Cite this

Aoyama, T., Liang, B., Okamoto, T., Matsusaki, T., Nishijo, K., Ishibe, T., ... Toguchida, J. (2005). PGE2 signal through EP2 promotes the growth of articular chondrocytes. Journal of Bone and Mineral Research, 20(3), 377-389. https://doi.org/10.1359/JBMR.041122

PGE2 signal through EP2 promotes the growth of articular chondrocytes. / Aoyama, Tomoki; Liang, Bojian; Okamoto, Takeshi; Matsusaki, Takashi; Nishijo, Koichi; Ishibe, Tatsuya; Yasura, Ko; Nagayama, Satoshi; Nakayama, Tomitaka; Nakamura, Takashi; Toguchida, Junya.

In: Journal of Bone and Mineral Research, Vol. 20, No. 3, 03.2005, p. 377-389.

Research output: Contribution to journalArticle

Aoyama, T, Liang, B, Okamoto, T, Matsusaki, T, Nishijo, K, Ishibe, T, Yasura, K, Nagayama, S, Nakayama, T, Nakamura, T & Toguchida, J 2005, 'PGE2 signal through EP2 promotes the growth of articular chondrocytes', Journal of Bone and Mineral Research, vol. 20, no. 3, pp. 377-389. https://doi.org/10.1359/JBMR.041122
Aoyama, Tomoki ; Liang, Bojian ; Okamoto, Takeshi ; Matsusaki, Takashi ; Nishijo, Koichi ; Ishibe, Tatsuya ; Yasura, Ko ; Nagayama, Satoshi ; Nakayama, Tomitaka ; Nakamura, Takashi ; Toguchida, Junya. / PGE2 signal through EP2 promotes the growth of articular chondrocytes. In: Journal of Bone and Mineral Research. 2005 ; Vol. 20, No. 3. pp. 377-389.
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