Abstract
Fibrillin-1 (FBN1) deficiency-induced systemic sclerosis is attributed to elevation of interleukin-4 (IL4) and TGF-β, but the mechanism underlying FBN1 deficiency-associated osteopenia is not fully understood. We show that bone marrow mesenchymal stem cells (BMMSCs) from FBN1-deficient (Fbn1(+/-)) mice exhibit decreased osteogenic differentiation and increased adipogenic differentiation. Mechanistically, this lineage alteration is regulated by IL4/IL4Rα-mediated activation of mTOR signaling to down-regulate RUNX2 and up-regulate PPARγ2, respectively, via P70 ribosomal S6 protein kinase (P70S6K). Additionally, we reveal that activation of TGF-β/SMAD3/SP1 signaling results in enhancement of SP1 binding to the IL4Rα promoter to synergistically activate mTOR pathway in Fbn1(+/-) BMMSCs. Blockage of mTOR signaling by osteoblastic-specific knockout or rapamycin treatment rescues osteopenia phenotype in Fbn1(+/-) mice by improving osteogenic differentiation of BMMSCs. Collectively, this study identifies a previously unrecognized role of the FBN1/TGF-β/IL4Rα/mTOR cascade in BMMSC lineage selection and provides experimental evidence that rapamycin treatment may provide an anabolic therapy for osteopenia in Fbn1(+/-) mice.
© 2015 Chen et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipogenesis / drug effects
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Adipogenesis / genetics
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Animals
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Bone Diseases, Metabolic / genetics
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Bone Diseases, Metabolic / metabolism*
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cells, Cultured
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Female
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Fibrillin-1
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Fibrillins
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Flow Cytometry
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Immunoblotting
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Immunosuppressive Agents / pharmacology
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Male
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Microscopy, Fluorescence
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Osteogenesis / drug effects
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Osteogenesis / genetics
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RNA Interference
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Scleroderma, Systemic / genetics
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Scleroderma, Systemic / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Transforming Growth Factor beta / metabolism
Substances
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Fbn1 protein, mouse
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Fibrillin-1
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Fibrillins
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Il4ra protein, mouse
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Immunosuppressive Agents
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Microfilament Proteins
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Receptors, Cell Surface
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Transforming Growth Factor beta
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Sirolimus