mTOR inhibition rescues osteopenia in mice with systemic sclerosis

J Exp Med. 2015 Jan 12;212(1):73-91. doi: 10.1084/jem.20140643. Epub 2014 Dec 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis / drug effects
  • Adipogenesis / genetics
  • Animals
  • Bone Diseases, Metabolic / genetics
  • Bone Diseases, Metabolic / metabolism*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Female
  • Fibrillin-1
  • Fibrillins
  • Flow Cytometry
  • Immunoblotting
  • Immunosuppressive Agents / pharmacology
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Microscopy, Fluorescence
  • Osteogenesis / drug effects
  • Osteogenesis / genetics
  • RNA Interference
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Fbn1 protein, mouse
  • Fibrillin-1
  • Fibrillins
  • Il4ra protein, mouse
  • Immunosuppressive Agents
  • Microfilament Proteins
  • Receptors, Cell Surface
  • Transforming Growth Factor beta
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Sirolimus