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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Hong, Suk-hyun Stevens, Hazel Y. Nofsinger, Russell Dvorak-ewell, Melita Evans, Ronald M. Frangos, John A. Shoback, Dolores Barish, Grant D. Castro, Glenda L. |
| Description | Author Affiliation: Hong SH ( Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.); |
| Abstract | Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-ß and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 47 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Bone Marrow Metabolism Cytokines Epigenetic Repression Physiology Nuclear Receptor Co-Repressor 2 Antagonists & Inhibitors Primary Myelofibrosis Drug Therapy Signal Transduction Thrombopoietin Genetics Alkaline Phosphatase Blood Animals Calcium Cell Proliferation Drug Effects DNA Primers Enzyme-Linked Immunosorbent Assay Gene Expression Profiling Gene Knock-In Techniques Luciferases Megakaryocytes Mice Organic Chemicals Platelet-Derived Growth Factor Polymerase Chain Reaction Etiology Biosynthesis Transforming Growth Factor Beta Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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