title: Discovering small molecules that inhibit adipogenesis and promote osteoblastogenesis: unique screening and Oncostatin M-like activity.
abstract: Oncostatin M (OSM), one of the IL-6 family cytokines, inhibits adipogenic differentiation and stimulates osteoblastogenic differentiation from human bone marrow mesenchymal stem cells (hBMSCs). This functional study of OSM enabled us to develop a two-dimensional small-molecule screen that shifts hBMSC differentiation from adipocyte to osteoblast. Several structurally related compounds (isoxazoles) inhibited the accumulation of intracellular lipid droplets, whereas they promoted alkaline phosphatase activity and extracellular matrix calcification. Isoxazoles also reduced the expression of adipogenic transcription factor PPARγ and increased the levels of osteogenic transcription factors Runx2 and Osterix. They also induced the expression of the Wnt/β-catenin downstream gene and TOPflash reporter; however, the dephosphorylated β-catenin-active form was not significantly increased. Interestingly, the slight modification of the active compound led to a complete reversion of the dual differentiation activities. In summary, we have identified isoxazoles with anti-adipogenic and pro-osteogenic activities that provide a potential new tool for exploring the lineage commitment of mesenchymal stem cells and a possible lead for therapeutic intervention in osteopenia and osteoporosis.
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: nawa.katsuhiko.cs@daiichisankyo.co.jp.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nawa
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ikeno
authors.forename: Norikazu
authors.initials: N
authors.lastname: Matsuhashi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ogasawara
authors.forename: Eri
authors.initials: E
authors.lastname: Otsuka
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000469:Alkaline Phosphatase / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007555:Isoxazoles / Q000302:isolation & purification / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053683:Oncostatin M / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D007555:Isoxazoles; D047495:PPAR gamma; C493709:RUNX2 protein, human; D054852:Small Molecule Libraries; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; D014157:Transcription Factors; D051176:beta Catenin; D053683:Oncostatin M; D000469:Alkaline Phosphatase
keywords: ALP; Adipogenesis; C/EBP; CCAAT/enhancer-binding protein; GSK; IL-11; IL-6; Interleukin-11; Interleukin-6; Isoxazole; LEF; LIF; MSC; Mesenchymal stem cell; OSM; Oncostatin M; Osteogenesis; Osterix; Osx; PPAR; Runx; T-cell factor; TCF; alkaline phosphatase; glycogen synthase kinase; leukemia inhibitory factor; lymphoid enhancer factor; mesenchymal stem cell; peroxisome proliferator-activated receptor; runt-related transcription factor