title: Regulation of human bone marrow stromal cell proliferation and differentiation capacity by glucocorticoid receptor and AP-1 crosstalk.
abstract: Although marrow adipocytes and osteoblasts derive from a common bone marrow stromal cells (BMSCs), the mechanisms that underlie osteoporosis-associated bone loss and marrow adipogenesis during prolonged steroid treatment are unclear. We show in human BMSCs (hBMSCs) that glucocorticoid receptor (GR) signaling in response to high concentrations of glucocorticoid (GC) supports adipogenesis but inhibits osteogenesis by reducing c-Jun expression and hBMSC proliferation. Conversely, significantly lower concentrations of GC, which permit hBMSC proliferation, are necessary for normal bone mineralization. In contrast, platelet-derived growth factor (PDGF) signaling increases both JNK/c-Jun activity and hBMSC expansion, favoring osteogenic differentiation instead of adipogenesis. Indeed, PDGF antagonizes the proadipogenic qualities of GC/GR signaling. Thus our results reveal a novel c-Jun-centered regulatory network of signaling pathways in differentiating hBMSCs that controls the proliferation-dependent balance between osteogenesis and adipogenesis.
authors.affiliation: Fundación Inbiomed, Foundation for Stem Cell Research, Mesenchymal and Hematopoietic Stem Cell Department, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Cárcamo-Orive
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Gaztelumendi
authors.forename: Jesús
authors.initials: J
authors.lastname: Delgado
authors.forename: Naiara
authors.initials: N
authors.lastname: Tejados
authors.forename: Akaitz
authors.initials: A
authors.lastname: Dorronsoro
authors.forename: Jon
authors.initials: J
authors.lastname: Fernández-Rueda
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
authors.forename: César
authors.initials: C
authors.lastname: Trigueros
mesh_terms: D050156:Adipogenesis / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005434:Flow Cytometry; D006801:Humans; D010012:Osteogenesis / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology*; D018808:Transcription Factor AP-1 / Q000502:physiology*
chemical_list: D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1