[show abstract][hide abstract] ABSTRACT: Activation of fibroblast growth factor receptor 3 (FGFR3) leads to attenuation of cartilage growth. The members of the STAT family of transcription factors are believed to participate in FGFR3 signaling in cartilage, however the molecular mechanism of this action is poorly understood. Here, we demonstrate that a chronic FGF stimulus leads to accumulation of STAT1, 3, 5 and 6, evident in both in vitro chondrocyte model and murine limb explant cultures. Despite the accumulation, both endogenous and cytokine-induced activation of STAT1 and STAT3 is impaired by FGF, as demonstrated by imaging of active STAT nuclear translocation and analyses of STAT activatory phosphorylation and transcriptional activation. Further, we demonstrate that FGF induces expression of CIS, SOCS1 and SOCS3 inhibitors of gp130, a common receptor for the IL6-family of cytokines. Since cytokine-gp130 signaling represents an important positive regulator of cartilage, its inhibition may contribute to the growth-inhibitory effect of FGFR3 in cartilage.
[show abstract][hide abstract] ABSTRACT: Over the past several years, the C-natriuretic peptide (CNP) has emerged as an important regulator of cartilage homeostasis and endochondral bone growth. In mice, genetic ablation of CNP or its cognate receptor NPRB results in marked dwarfism. When a downstream component of CNP signaling, protein kinase-G II (PKGII), is removed from cartilage, the mice have disturbed chondrocyte proliferation and cartilage matrix production. In contrast, activating mutations in PKGII as well as overexpression of CNP result in significant skeletal overgrowth in mice, demonstrating the positive role of CNP signaling in regulation of mammalian chondrocyte proliferation and cartilage matrix production. This is further supported by the existence of a human dwarfism, acromesomelic dysplasia Maroteaux-type (MIM #602875) that is caused by loss-of-function of NPRB. In comparison with other signaling systems, the molecular basis of CNP signaling in cartilage remains largely unknown, thus leaving many important questions open for future investigation. This review summarizes our current knowledge about the mechanism of CNP signaling in cartilage, areas for future investigation and its potential therapeutic uses.
Molecular Genetics and Metabolism 12/2007; 92(3):210-5. · 2.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Erk MAP kinase pathway contributes to tumor development and thus represents an important therapeutic target. Several inhibitors of the Erk pathway are presently being evaluated in clinical trials for cancer, but show limited efficiency thus warranting discovery of more potent inhibitors. We have developed a novel mammalian cell-based assay that should facilitate the identification of such compounds by screening molecular libraries. In rat chondrosarcoma (RCS) cells, treatment with fibroblast growth factor 2 (FGF2) leads to sustained activation of the Erk pathway, resulting in growth arrest with more than an 80% cell count difference between control and FGF2-treated cells after 72 h of treatment. The extent of both Erk activation and the growth arrest can be precisely modulated by the FGF2 dose. We also demonstrate that FGF2-mediated activation of the Erk pathway is robust and has only a limited sensitivity to the available MEK inhibitors. The assay is rapid, sensitive and easily adapted to high throughput screening. A major advantage of this system is exclusion of toxic compounds as false-positive hits, given the nature of the RCS response to inhibition of the Erk pathway, i.e. growth.
Investigational New Drugs 09/2007; 25(4):391-5. · 3.50 Impact Factor