GRIP1 enhances estrogen receptor α-dependent extracellular matrix gene expression in chondrogenic cells

M. Kato, H. Takaishi, Masaki Yoda, T. Tohmonda, J. Takito, Nobuyuki Fujita, N. Hosogane, Keisuke Horiuchi, T. Kimura, Yasunori Okada, T. Saito, H. Kawaguchi, T. Kikuchi, M. Matsumoto, Yoshiaki Toyama, K. Chiba

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Objective: The role of postmenopause on the pathogenesis of cartilage degeneration has been an open question. We assessed cartilage degeneration in estrogen receptor (ER)α null mice and examined the role of glucocorticoid receptor-interacting protein 1 (GRIP1) in the ERα-dependent transcription of a type II collagen gene (col2a1) with special reference to a crosstalk with the transforming growth factor (TGF)-β signaling pathway. Methods: The vertebral cartilaginous endplate from female ERα null mice was subjected to histological analyses. Col2a1 expression of primary chondrocytes (PCs) obtained from ERα null mice after 17β-estradiol (E2) and TGF-β1 stimulation was examined by reverse transcription polymerase chain reaction (RT-PCR). Estrogen response element (ERE) or col2a1 promoter-enhancer luciferase reporter system was used to investigate the crosstalk among ERα, GRIP1, and MKK6. Col2a1 expression and glycosaminoglycan (GAG) content were measured in ATDC5 cells treated with GRIP1 small interfering RNA (siRNA). Results: ERα deficiency clearly accelerated impairment of the vertebral cartilaginous endplate. E2 and TGF-β1 stimulation increased col2a1 expression in PC from wild-type mice, but not that from ERα null mice. The same stimulation increased the col2a1 promoter-enhancer reporter activity, and the elevated activity was decreased by dominant-negative ERα and p38 mitogen-activated protein kinase (MAPK) inhibitor. GRIP1 increased the E2-dependent ERE activation in the presence of ERα and constitutive-active MKK6. GRIP1 siRNA repressed col2a1 expression and GAG production in ATDC5 cells. Conclusions: Crosstalks between ERα/GRIP1 and TGF-β/MKK6/p38 MAPK pathway have protective roles on cartilage metabolism via regulating the extracellular matrices expression. The finding may lead to the development of a novel therapeutic approach for cartilage degeneration.

Original languageEnglish
Pages (from-to)934-941
Number of pages8
JournalOsteoarthritis and Cartilage
Issue number7
Publication statusPublished - 2010 Jul


  • Cartilaginous endplate
  • Chondrocyte
  • Estrogen receptor
  • GRIP1
  • Intervertebral disc
  • MKK6

ASJC Scopus subject areas

  • Rheumatology
  • Biomedical Engineering
  • Orthopedics and Sports Medicine


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