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

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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 - 2015

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Metabolic Bone Diseases
Systemic Scleroderma
Mesenchymal Stromal Cells
Bone Marrow
Sirolimus
Interleukin-4
Ribosomal Protein S6 Kinases
Cell Lineage
Up-Regulation
Down-Regulation
Phenotype
Fibrillin-1
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

mTOR inhibition rescues osteopenia in mice with systemic sclerosis. / Chen, Chider; Akiyama, Kentaro; Wang, Dandan; Xu, Xingtian; Li, Bei; Moshaverinia, Alireza; Brombacher, Frank; Sun, Lingyun; Shi, Songtao.

In: Journal of Experimental Medicine, Vol. 212, No. 1, 2015, p. 73-91.

Research output: Contribution to journalArticle

Chen, C, Akiyama, K, Wang, D, Xu, X, Li, B, Moshaverinia, A, Brombacher, F, Sun, L & Shi, S 2015, 'mTOR inhibition rescues osteopenia in mice with systemic sclerosis', Journal of Experimental Medicine, vol. 212, no. 1, pp. 73-91. https://doi.org/10.1084/jem.20140643
Chen, Chider ; Akiyama, Kentaro ; Wang, Dandan ; Xu, Xingtian ; Li, Bei ; Moshaverinia, Alireza ; Brombacher, Frank ; Sun, Lingyun ; Shi, Songtao. / mTOR inhibition rescues osteopenia in mice with systemic sclerosis. In: Journal of Experimental Medicine. 2015 ; Vol. 212, No. 1. pp. 73-91.
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AU - Moshaverinia, Alireza

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AU - Sun, Lingyun

AU - Shi, Songtao

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