RESUMO
Accelerated marrow adipogenesis has been associated with ageing and osteoporosis and is thought to be because of an imbalance between adipogenic and osteogenic differentiation of mesenchymal stem cell (MSCs). We have previously found that lysyl oxidase (Lox) inhibition disrupts BMP4-induced adipocytic lineage commitment and differentiation of MSCs. In this study, we found that lox inhibition dramatically up-regulates BMP4-induced expression of CCAAT/enhancer binding protein (C/EBP) homologous protein 10 (CHOP-10), which then promotes BMP4-induced osteogenesis of MSCs both in vitro and in vivo. Specifically, Lox inhibition or CHOP-10 up-regulation activated Wnt/ß-catenin signalling to enhance BMP4-induced osteogenesis, with pro-adipogenic p38 MAPK and Smad signalling suppressed. Together, we demonstrate that Lox/CHOP-10 crosstalk regulates BMP4-induced osteogenic and adipogenic fate determination of MSCs, presenting a promising therapeutic target for osteoporosis and other bone diseases.
Assuntos
Proteína Morfogenética Óssea 4/genética , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Proteína-Lisina 6-Oxidase/genética , Fator de Transcrição CHOP/genética , Adipócitos/metabolismo , Adipogenia/genética , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos , Osteoporose/genética , Osteoporose/patologia , Osteoporose/terapia , Via de Sinalização Wnt/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
OBJECTIVE: The recruitment and commitment of mesenchymal stem cells and their terminal differentiation into adipocytes are the main pathways for increasing adipocyte cell numbers during obesity. Our previous studies have shown that lysyl oxidase (Lox) is upregulated and functions as an essential factor during bone morphogenetic protein 4 (BMP4) -induced C3H10T1/2 cell adipocytic lineage commitment. However, the mechanism of Lox regulation during adipogenic lineage commitment has remained largely unestablished. METHODS: Samples of adipose tissue from humans with different BMI and C57BL/6 mice with a high-fat diet were used to compare microRNA-27 (miR-27) expression level associated with obesity. Taqman assays were used for miR-27 expression detection and Oil Red O staining for adipogenesis analysis. RESULTS: A negative correlation was identified between Lox expression level and miR-27 expression in both BMP4-treated C3H10T1/2 cells and human subcutaneous adipose tissues. A Lox 3' UTR luciferase reporter assay showed that miR-27 directly targeted Lox. Furthermore, overexpression of miR-27 impaired BMP4-induced upregulation of Lox and adipocytic commitment, which could be rescued by overexpression of mature Lox. Conversely, miR-27 inhibition by specific inhibitors increased Lox expression and adipocytic commitment. CONCLUSIONS: Taken together, these results suggest a novel role for miR-27 in repressing adipogenic lineage commitment by targeting Lox.