Bioactive Silica Nanoparticles Promote Osteoblast Differentiation through Stimulation of Autophagy and Direct Association with LC3 and p62

被引:165
作者
Ha, Shin-Woo [2 ]
Weitzmann, M. Neale [1 ,2 ,3 ]
Beck, George R., Jr. [1 ,2 ,3 ]
机构
[1] Atlanta Dept Vet Affairs Med Ctr, Decatur, GA 30033 USA
[2] Emory Univ, Div Endocrinol, Dept Med, Atlanta, GA 30322 USA
[3] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA
关键词
silica nanoparticles; endocytosis; ERK1/2; autophagy; LC3; beta; p62; osteoblast differentiation; CELLULAR UPTAKE; PROTEIN-DEGRADATION; GOLD NANOPARTICLES; CELLS; EXPRESSION; NANOMATERIALS; SUPPRESSION; ACTIVATION; INHIBITION; LYSOSOMES;
D O I
10.1021/nn5009879
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
We recently identified an engineered bioactive silica-based nanoparticle formulation (designated herein as NP1) that stimulates in vitro differentiation and mineralization of osteoblasts, the cells responsible for bone formation, and increases bone mineral density in young mice in vivo. The results demonstrate that these nanoparticles have intrinsic biological activity; however, the intracellular fate and a complete understanding of the mechanism(s) involved remains to be elucidated. Here we investigated the cellular mechanism(s) by which NP1 stimulates differentiation and mineralization of osteoblasts. We show that NP1 enters the cells through a caveolae-mediated endocytosis followed by stimulation of the mitogen activated protein kinase ERK1/2 (p44/p42). Our findings further revealed that NP1 stimulates autophagy including the processing of LC3 beta-I to LC3 beta-II, a key protein involved in autophagosome formation, which is dependent on ERK1/2 signaling. Using a variant of NP1 with cobalt ferrite magnetic metal core (NP1-MNP) to pull down associated proteins, we found direct binding of LC3 beta and p62, two key proteins involved in autophagosome formation, with silica nanoparticles. Interestingly, NP1 specifically interacts with the active and autophagosome associated form of LC3 beta (LC3 beta-II). Taken together, the stimulation of autophagy and associated signaling suggests a cellular mechanism for the stimulatory effects of silica nanoparticles on osteoblast differentiation and mineralization.
引用
收藏
页码:5898 / 5910
页数:13
相关论文
共 65 条
  • [1] Alcantar NA, 2000, J BIOMED MATER RES, V51, P343, DOI 10.1002/1097-4636(20000905)51:3<343::AID-JBM7>3.0.CO
  • [2] 2-D
  • [3] Bioactive silica-based nanoparticles stimulate bone-forming osteoblasts, suppress bone-resorbing osteoclasts, and enhance bone mineral density in vivo
    Beck, George R., Jr.
    Ha, Shin-Woo
    Camalier, Corinne E.
    Yamaguchi, Masayoshi
    Li, Yan
    Lee, Jin-Kyu
    Weitzmann, M. Neale
    [J]. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE, 2012, 8 (06) : 793 - 803
  • [4] Beck GR, 1998, J CELL BIOCHEM, V68, P269, DOI 10.1002/(SICI)1097-4644(19980201)68:2<269::AID-JCB13>3.0.CO
  • [5] 2-A
  • [6] Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases
    Cargnello, Marie
    Roux, Philippe P.
    [J]. MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, 2011, 75 (01) : 50 - 83
  • [7] Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes
    Chithrani, B. Devika
    Chan, Warren C. W.
    [J]. NANO LETTERS, 2007, 7 (06) : 1542 - 1550
  • [8] The effect of surface charge on the uptake and biological function of mesoporous silica nanoparticles 3T3-L1 cells and human mesenchymal stem cells
    Chung, Tsai-Hua
    Wu, Si-Han
    Yao, Ming
    Lu, Chen-Wen
    Lin, Yu-Shen
    Hung, Yann
    Mou, Chung-Yuan
    Chen, Yao-Chang
    Huang, Dong-Ming
    [J]. BIOMATERIALS, 2007, 28 (19) : 2959 - 2966
  • [9] Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity
    Corcelle, Elisabeth
    Nebout, Marielle
    Bekri, Soumeya
    Gauthier, Nils
    Hofman, Paul
    Poujeol, Philippe
    Fenichel, Patrick
    Mograbi, Baharia
    [J]. CANCER RESEARCH, 2006, 66 (13) : 6861 - 6870
  • [10] PARTICIPATION OF LYSOSOMES IN CELLULAR AUTOPHAGY INDUCED IN RAT LIVER BY GLUCAGON
    DETER, RL
    BAUDHUIN, P
    DEDUVE, C
    [J]. JOURNAL OF CELL BIOLOGY, 1967, 35 (2P1) : C11 - &