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

mTOR inhibition rescues osteopenia in mice with systemic sclerosis.

Author information

1
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033 Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
2
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033 Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Kita-ku, Okayama 700-8525, Japan.
3
Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
4
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033 Key Laboratory of Translational Research, Tong Ji University School of Stomatology, Shanghai 200072, China.
5
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033 School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
6
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033.
7
Division of Immunology, Cape Town Component and Institute of Infectious Diseases and Molecular Medicine (IIDMM), International Center for Genetic Engineering and Biotechnology (ICGEB) University of Cape Town, Cape Town 7925, South Africa.
8
Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China songtaos@dental.upenn.edu lingyunsun2012@163.com.
9
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033 songtaos@dental.upenn.edu lingyunsun2012@163.com.

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.

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PMID:
25534817
PMCID:
PMC4291526
DOI:
10.1084/jem.20140643
[Indexed for MEDLINE]
Free PMC Article

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