During osteoporosis, fat mass and obesity-associated protein (FTO) promotes the shift of bone marrow mesenchymal stem cells to adipocytes and represses osteoblast activity. However, the role and mechanisms of FTO on osteoclast formation and bone resorption remain unknown. In this study, we investigated the effect of FTO on RAW264.7 cells and bone marrow monocytes (BMMs)-derived osteoclasts in vitro and observed the influence of FTO on ovariectomized (OVX) mice model to mimic postmenopausal osteoporosis in vivo. Results found that FTO was up-regulated in BMMs from OVX mice. Double immunofluorescence assay showed co-localization of FTO with tartrate-resistant acid phosphatase (TRAP) in femurs of OVX mice. FTO overexpression enhanced TRAP-positive osteoclasts and F-actin ring formation in RAW264.7 cells upon RANKL stimulation. The expression of osteoclast differentiation-related genes, including nuclear factor of activated T cells c1 (NFATc1) and c-FOS, was upregulated in BMMs and RAW264.7 cells after FTO overexpression. FTO overexpression induced the phosphorylation and nuclear translocation of factor-kappa B (NF-κB) p65 in BMMs and RAW264.7 cells exposed to RANKL. ChIP and dual-luciferase assays revealed that FTO overexpression contributed to RANKL-induced binding of NF-κB to NFATc1 promoter. Rescue experiments suggested that FTO overexpression-mediated osteoclast differentiation was suppressed after intervention with a NF-κB inhibitor pyrrolidine dithiocarbamate . Further in vivo evidence revealed that FTO knockdown increased bone trabecula and bone mineral density, inhibited bone resorption and osteoclastogenesis in osteoporotic mice. Collectively, our research demonstrates that downregulated FTO inhibits bone resorption and osteoclastogenesis through NF-κB inactivation, which provides a novel reference for osteoporosis treatment.
Using poly(acrylic acid) (abbreviated as PAA) as a shell, bimodal mesoporous silicas (abbreviated as BMMs) as a core, and bipyridine-proline (abbreviated as Z) as an active species, a facile approach for preparation of the [email protected] nanocomposites with core–shell structure was proposed, which was used as a suitable pH-sensitive catalyst for asymmetric aldol reaction between p-nitrobenzaldehyde and cyclohexanone. Their microstructural features and physicochemical properties were extensively characterized by various methods, such as powder X-ray diffraction patterns, N 2 adsorption–desorption isotherms, the scanning (and transmission) electron microscopy images, the dynamic light scattering measurements, the thermogravimetric analysis, the elemental analysis, and the Fourier transform infrared spectroscopy spectra. Particularly, their fractal evolution, the pair distance distribution function, and the Porod plots were demonstrated via the small-angle X-ray scattering patterns. The results elucidated that the PAA was successfully incorporated onto the external amino-modified surfaces of the mesoporous BMMs, and the particles having PAA grafted thereon had a pH-responsive shell in thickness of around 0.97 nm for controlled release of Z species by adjusting pH value of the reaction medium. Besides, the synthesized [email protected] presented the satisfactory catalytic yields (around 80%) in comparison with the homo- and heterogeneous catalytic system using Z or [email protected] as the catalysts.
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