Defective gp130-mediated Signal Transducer and Activator of Transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation

Matthias Ernst, Melissa Inglese, Paul Waring, Ian K. Campbell, Shisan Bao, Fiona J. Clay, Warren S. Alexander, Ian P. Wicks, David M. Tarlinton, Ulrike Novak, Joan K. Heath, Ashley R. Dunn

Research output: Contribution to journalArticleResearchpeer-review

205 Citations (Scopus)


The receptor subunit gp130 transduces multiple cell type-specific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator of transcription (STAT) and src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130ΔSTAT "knock-in" mutation which deleted all STAT-binding sites. gp130ΔSTAT mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130ΔSTAT mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cytokines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130ΔSTAT mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130.

Original languageEnglish
Pages (from-to)189-203
Number of pages15
JournalJournal of Experimental Medicine
Issue number2
Publication statusPublished - 16 Jul 2001
Externally publishedYes


  • Gene targeting
  • Infertility
  • Interleukin
  • Signal transduction
  • STAT

Cite this