Degenerative joint disease following defective cytokine receptor signaling
- Randy Cron1
© Biomed Central Ltd 2001
Received: 10 August 2001
Accepted: 10 September 2001
Published: 10 September 2001
IL-6 family members signal through the common gp130 ? chain receptor, which possesses multiple signaling domains. To study cytokine signaling in vivo via signal transducer and activator of transcription (STAT) proteins, gp130?STAT mice were generated by 'knocking in' a mutant construct lacking all four gp130 STAT binding sites; this was necessary as gp130 knockout die as embryos (see Additional information ).
The gp130?STAT/?STAT 'knock-in' mice were viable with shortened life spans; similar to IL-6-null mice (see Additional information ), these mice exhibit impaired humoral and mucosal immunity, and like leukemia inhibitory factor (LIF)-deficient females (see Additional information ) were infertile. Surprisingly, these mice displayed gastrointestinal tract ulcerations and severe joint patholog; 60% developed bilateral arthritis of large weight bearing joints. Histopathology revealed cartilaginous nodules, erosions, and synovial hyperplasia but few inflammatory cells. The authors surmise that joint pathology was primarily a result of synovial hyperplasia. Synovial fibroblasts from gp130?STAT/?STAT mice demonstrated increased proliferation in response to IL-6 or LIF, and this correlated with prolonged activity of mitogen-activated protein kinase family members, Erk-1 and Erk-2, as well as SHP-2, a phosphatase that also binds gp130. The authors hypothesized that the lack of STAT binding to gp130 results in a lack of autoinhibitory feedback on all signaling mediated by gp130, including activation of Erk via SHP-2 and ras. This is indirectly tested by analyzing suppressor of cytokine signaling (SOCS) levels in cytokine-stimulated synovial cells from gp130?STAT/?STAT mice. SOCS proteins are normally increased by activated STAT proteins and inhibit gp130 activity. Interestingly, SOCS-1 was decreased in gp130?STAT/?STAT cells. Increased c-fos promoter activity, an indirect measure of Erk activity, was noted in IL-6 stimulated gp130?STAT/?STAT synovial cells and was inhibited by SOCS-1 overexpression. The authors concluded that decreased STAT-mediated SOCS induction, causing sustained Erk activation, leads to synovial overgrowth and degenerative joint disease.
This paper reports a degenerative arthritis model in a mouse with defective STAT signaling via gp130. Future studies of these mice have the advantage of being able to analyse a spontaneous model of arthritis in which cartilage defects, synovial cell hyperplasia, and erosive joint disease occur. The results may provide insight to synovial cell hyperplasia in a variety of chronic human arthritides. The paper also demonstrates the importance of feedback inhibition of signaling molecules and suggests that targeting SOCS proteins may work to block some cytokine-mediated arthritis.
Gene targeting/knock-in mice, histopathology, 3H-thymidine incorporation, western blot, northern blot, ELISA, transient transfection
Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T, Nakahata T, Hirabayashi T, Yoneda Y, Tanaka K, Wang WZ, Mori C, Shiota K, Yoshida N, Kishimoto T: Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders.
Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Kohler G: Impaired immune and acute-phase responses in interleukin-6-deficient mice.
Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, Abbondanzo SJ: Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor.
Nature 1992, 359:76-79 (PubMed abstract).
- Ernst M, Inglese M, Waring P, Campbell IK, Bao S, Clay FJ, Alexander WS, Wicks IP, Tarlinton DM, Novak U, Heath JK, Dunn AR: Defective gp130-mediated signal transducer of activator of transcription (STAT) signaling results in degenerative joint, disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med. 2001, 194: 189-203.PubMedPubMed CentralView ArticleGoogle Scholar