PCI-34051 The phenotypes of KD Ddr transgenic
The phenotypes of KD-Ddr2 transgenic mice were less severe than expected from the results of miDdr2-transfected ATDC5 cells, which indicated that DDR2 might play important roles in endochondral ossification but neither critical nor essential roles in determining total body and skeleton size.
The greater thickness of the proliferative chondrocyte layer in KD-Ddr2 transgenic mice could be an anomaly in the reduction of chondrocyte proliferation in DDR2-deficient mice . This difference could come from regional and functional differences in DDR2 shortage; these differences indicate that DDR2 could have various roles in different conditions, either systemically or locally.
To summarize, we investigated the effects of both the decrement of DDR2 in miDdr2-transfected ATDC5 cells in vitro and in DDR2 dominant-negative overexpressed transgenic mice, and the results suggested that DDR2 might regulate proliferative chondrocytes.
Acknowledgments The α2 (XI) collagen gene-based expression vector, 742lacZInt, was kindly gifted from Dr. Tsumaki (Osaka University). The research was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Cultures, Sports, Science, and Technology of Japan; by the Morinaga Foundation; and by the Foundation for Growth Science.
Introduction Idiopathic pulmonary fibrosis (IPF), the most common fibrotic conditions in the lung, is a chronic and lethal human disease with unknown etiology. IPF patients have a median survival of ∼2–3 years after diagnosis because of an irreversible loss of lung function and respiratory failure. Although a variety of inflammatory insults are associated with the development of IPF, an undeniable fact is that this type fibrotic disorder is clinically recalcitrant to treatment with immunosuppressive agents, leading to the recent shift of concept for IPF treatment away from anti-inflammation toward antifibrosis. However, although there has been a huge rise in clinical trials with antifibrotic drugs during the past decade, it was until recently that two pharmacological agents were approved for the treatment of moderate IPF. The pathogenesis of pulmonary fibrosis involves alveolar epithelial cell injury, inflammatory cell infiltration, as well as fibroblast recruitment and activation. It has been long accepted that the activated fibroblasts (so-called myofibroblasts), characterized by de novo expression of α-smooth muscle PCI-34051 (α-SMA), are the key effector cells in various fibrotic diseases in which they have stronger contractile activity and are responsible for the secretion of exaggerated amounts of extracellular matrix (ECM) molecules with the subsequent scaring and destruction of the tissue architecture. The formation of myofibroblasts can be driven by cytokines, matrix proteins, and biomechanical tension. Among these myofibroblast-modulating factors, transforming growth factor (TGF)-β is considered to be the most powerful driver of fibroblast ECM production and tissue fibrosis characterized to date and agents blocking its activation have been under clinical trial for IPF. TGF-β regulates myofibroblast gene expression through canonical Smad pathway and non-Smad pathways such as mitogen-activated protein kinase family and PI3K/Akt. Recently, the dynamically altered ECM microenvironment was suggested to act as positive feedback stimuli for lung fibroblast behaviors and the progression of lung fibrosis., Because fibrillar collagens are major components of fibrotic lung matrices, understanding how fibroblasts or myofibroblasts receive and transmit signals from fibrillar collagens will definitely favor the development of novel drugs to intervene in the influence from abnormal ECM. Discoidin domain receptors (DDRs), including DDR1 and DDR2, are unique receptor tyrosine kinases because they signal in response to nondiffusible collagens rather than diffusible cytokines. Unlike the quick-on and quick-off activation pattern of growth factor receptors, DDRs display a slow but sustained kinetic of phosphorylation upon collagen binding, which induces cell differentiation, migration, and invasion. In contrast to DDR1 that is primarily expressed in epithelial cells and activated by multiple types of collagens, DDR2 is abundantly expressed in fibroblasts or cells of mesenchymal origin and activated by fibrillar collagens and type X collagen., Accumulating evidences indicate that DDR2 acts as a marker as well as a key regulator of epithelial mesenchymal transition (EMT).,,, The deficient expression of DDR2 in vivo can not only cause some developmental defects such as dwarfing and infertility,,, but also lead to several pathological changes, such as tumor progression, arthritis, and choroidal neovascularization.,,, Previous development or search of DDR-targeting drugs has yielded several candidate compounds,,,, most of which do not distinguish DDR1 from DDR2. Dasatinib, a Food and Drug Administration (FDA)-approved drug used to treat chronic myelocytic leukemia, was reported to potently inhibit the kinase activity of DDRs. Two recent clinical studies demonstrated that the lung cancer patients who carry oncogenic mutations of DDR2 showed response to dasatinib treatment.,