mTOR inhibition rescues osteopenia in mice with systemic sclerosis

Chider Chen, Kentaro Akiyama, Dandan Wang, Xingtian Xu, Bei Li, Alireza Moshaverinia, Frank Brombacher, Lingyun Sun, Songtao Shi

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)73-91
Number of pages19
JournalJournal of Experimental Medicine
Volume212
Issue number1
DOIs
Publication statusPublished - Jan 12 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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