mTOR inhibition rescues osteopenia in mice with systemic sclerosis

• Published in: The Journal of experimental medicine Vol. 212; no. 1; pp. 73 - 91
• Main Authors: Chen, Chider, Akiyama, Kentaro, Wang, Dandan, Xu, Xingtian, Li, Bei, Moshaverinia, Alireza, Brombacher, Frank, Sun, Lingyun, Shi, Songtao
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 12.01.2015
• Subjects: 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 Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal 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; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; RNA Interference; 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
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20140643

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.