Editors' ChoiceBone Disease

RAR Scars Bone Marrow

Sci. Signal.  26 Nov 2013:
Vol. 6, Issue 303, pp. ec288
DOI: 10.1126/scisignal.2004942

Primary myelofibrosis is a chronic disorder characterized by scarring of the bone marrow, ectopic hematopoiesis in the spleen, and anemia caused by the differentiation of abnormal blood cells. Current treatments include blood transfusions, bone marrow transplants, and pharmacological inhibition of the Jak (Janus kinase) pathway. Because this disease involves the bone marrow, which is the site for both hematopoietic and bone progenitor cells, retinoic acid (RA) signaling, a key regulator of both bone and blood cell proliferation and differentiation, may be involved. Hong et al. found that a “knock-in” mouse (SMRTmRID) with mutations in the transcriptional repressor SMRT (silencing mediator of retinoid and thyroid hormone receptor) that disrupt its ability to bind to the RA receptor (RAR) developed symptoms similar to human myelofibrosis. At 6 weeks old, the bones of SMRTmRID mice had decreased radial growth despite normal bone density and length and were more prone to fracture. Serum concentrations of osteoclast markers, the numbers of bone marrow osteoclasts, and the potential of progenitor cells to differentiate into osteoclasts in culture were also increased in thesemice. By 8 months old, SMRTmRID mice exhibited a loss of bone marrow hematopoetic stem cells and an increase in hematopoiesis in the spleen and had increased bone marrow fibrotic collagen and numbers of megakaryocytes and reticular cells in their bone cavities. Co-culture of wild-type mononuclear cells with bone marrow stroma from SMRTmRID mice induced megakaryocyte differentiation, and transplanting bone marrow from SMRTmRID mice into irradiated wild-type mice was sufficient to induce fibrosis. The gene encoding the cytokine thrombopoetin (TPO), a hormone that stimulates the differentiation of megakaryocytes, contained RAR response elements in its promoter and bound directly to RAR as determined by gel-shift assays and chromatin immunoprecipitation. TPO abundance was increased in the serum and bone marrow of SMRTmRID mice, and pharmacological inhibition of RAR with an orally available drug reduced Tpo expression and reversed bone defects, suggesting that derepression of endogenous RA signaling in the bone marrow microenvironment promotes cytokine production that leads to fibrosis.

S.-H. Hong, M. Dvorak-Ewell, H. Y. Stevens, G. D. Barish, G. L. Castro, R. Nofsinger, J. A. Frangos, D. Shoback, R. M. Evans, Rescue of a primary myelofibrosis model by retinoid-antagonist therapy. Proc. Natl. Acad. Sci. U.S.A. 110, 18820–18825 (2013). [Abstract] [Full Text]

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