A study on the molecular mechanism ofcytokine-mediated inhibition of osteoblast differentiation in rheumatoid arthritis

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591178
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Aichi Medical University
• Principal Investigator: YAMAMURA Masahiro Aichi Medical University, 医学部, 教授 (80252956)
• Project Period (FY): 2008 – 2010
• Keywords: 関節リウマチ / 骨芽細胞 / 炎症性サイトカイン / 骨形成蛋白質 / 腫瘍壊死因子 / Smad

Research Abstract

The cellular mechanism for cytokine-mediated inhibition of BMP-induced osteoblastic differentiation was investigated using mouse myoblast C2C12 cells. Osteoblast transformation of BMP-cultured C2C12 cells, and their Runx2/osteocalcin expression, ALP activity, and parathyroid hormone (PTH) responsiveness (cAMP production) were inhibited by TNF-α, but not by IL-1, IL-6, or IL-17. BMP-induced Smad1, 5, 8 phosphorylation in the cells was suppressed by TNF-α signaling, but inhibitory Smad6 gene activation was increased as determined by cDNA array. MAP kinase analysis showed that ERK1/ERK2 and SAPK/JNK phosphorylation were selectively activated in the cells with TNF-α. BMPs had no effect on TNF type 1 and 2 receptor-expression. Notably, SAPK/JNK inhibitors restored TNF-α inhibition of osteoblast differentiation, as demonstrated by Id-1-promoter activity as well as Runx2/osteocalcin mRNA levels. These results suggest that TNF-α may have a crucial role in BMP-induced osteogenic inhibition in the diseases such as rheumatoid arthritis, through its SAPK/JNK activation and Smad6 induction.

Research Products

• [Journal Article] Effect of infliximab on tumor necrosis factor-alpha-induced alterations in retinal microvascular endothelial cells and retinal pigment epithelial cells. (2010)
  • Author(s): Li H, Yoneda M, Takeyama M, Sugita I, Tsunekawa H, Yamada H, Watanabe D, Mukai T, Yamamura M, Iwaki M, Zako M.
  • Journal Title: J Ocul Pharmacol Ther 26(6) Pages: 549-556
• [Journal Article] Simvastatin antagonizes tumor necrosis factor-alpha inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway. (2008)
  • Author(s): Yamashita M, Otsuka F, Mukai T, Otani H, Inagaki K, Miyoshi T, Goto J, Yamamura M, Makino H.
  • Journal Title: J Endocrinol. 196(3) Pages: 601-613
• [Presentation] ヒト間葉系幹細胞の骨芽細胞分化に及ぼす炎症性サイトカインの作用 (2009)
  • Author(s): 向井知之、大塚文男、山村昌弘
  • Organizer: 第53回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2009-04-25
• [Remarks] ホームページ等