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- W2100359406 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." @default.
- W2100359406 created "2016-06-24" @default.
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- W2100359406 date "2014-12-22" @default.
- W2100359406 modified "2023-10-12" @default.
- W2100359406 title "mTOR inhibition rescues osteopenia in mice with systemic sclerosis" @default.
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- W2100359406 doi "https://doi.org/10.1084/jem.20140643" @default.
- W2100359406 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4291526" @default.
- W2100359406 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25534817" @default.
- W2100359406 hasPublicationYear "2014" @default.
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