Gene array identification of osteoclast genes: Differential inhibition of osteociastogenesis by cyclosporin a and granulocyte macrophage colony stimulating factor

被引:45
作者
Day, CJ
Kim, MS
Stephens, SRJ
Simcock, WE
Aitken, CJ
Nicholson, GC
Morrison, NA
机构
[1] Griffith Univ, Sch Hlth Sci, Southport, Qld 4215, Australia
[2] Univ Melbourne, Geelong Hosp, Dept Clin & Biomed Sci, Barwon Hlth, Geelong, Vic 3220, Australia
关键词
RANKL; NFAT; osteoclast; cyclosporin A; GM-CSF;
D O I
10.1002/jcb.10780
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Treatment of adherent peripheral blood mononuclear cells (PBMCs) with macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL) stimulates the formation of multinucleate osteoclast-like cells. Treatment with M-CSF alone results in the formation of macrophage-like cells. Through the use of Atlas human cDNA expression arrays, genes regulated by RANKL were identified. Genes include numerous cytokines and cytokine receptors (RANTES and CSF2Rproportional to), transcription factors (nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and GA binding protein transcription factor alpha (GABPalpha)), and ribosomal proteins (60S L17 and 40S S20). Real-time PCR analysis showed significant correlation (R-2 of 0.98 P<0.01) with array data for all genes tested. Time courses showed differential activation patterns of transcription factors with early induction of FUSE binding protein 1 (FBP) and c-Jun, and later steady upregulation of NFATc1 and GABP by RANKL. Treatment with cyclosporin A, a known NFATc1 inhibitor, resulted in a blockade of osteoclast formation. The mononuclear cells resulting from high cyclosporin treatment (1,000 ng/ml) were cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP) positive but expression of calcitonin receptor (CTR) was downregulated by more than 30-fold. Constant exposure of M-CSF- and RANKL-treated cells to GM-CSF resulted in inhibition of osteoclast formation and the downregulation of CTSK and TRAP implicating the upregulation of CSF2R in a possible feedback inhibition of osteoclastogenesis.
引用
收藏
页码:303 / 315
页数:13
相关论文
共 41 条
  • [1] Tissue-specific and ubiquitous promoters direct the expression of alternatively spliced transcripts from the calcitonin receptor gene
    Anusaksathien, O
    Laplace, C
    Li, X
    Ren, Y
    Peng, L
    Goldring, SR
    Galson, DL
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (25) : 22663 - 22674
  • [2] The structure of GABPα/β:: An ETS domain ankyrin repeat heterodimer bound to DNA
    Batchelor, AH
    Piper, DE
    de la Brousse, FC
    McKnight, SL
    Wolberger, C
    [J]. SCIENCE, 1998, 279 (5353) : 1037 - 1041
  • [3] Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony-stimulating factor and the ligand for the receptor activator of NFκB
    Cappellen, D
    Luong-Nguyen, NH
    Bongiovanni, S
    Grenet, O
    Wanke, C
    Susa, M
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (24) : 21971 - 21982
  • [4] SENSITIVITY TO VANADATE AND ISOFORMS OF SUBUNIT-A AND SUBUNIT-B DISTINGUISH THE OSTEOCLAST PROTON PUMP FROM OTHER VACUOLAR H+ ATPASES
    CHATTERJEE, D
    CHAKRABORTY, M
    LEIT, M
    NEFF, L
    JAMSAKELLOKUMPU, S
    FUCHS, R
    BARON, R
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (14) : 6257 - 6261
  • [5] Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression
    Decker, EL
    Nehmann, N
    Kampen, E
    Eibel, H
    Zipfel, PF
    Skerka, C
    [J]. NUCLEIC ACIDS RESEARCH, 2003, 31 (03) : 911 - 921
  • [6] Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency
    Gelb, BD
    Shi, GP
    Chapman, HA
    Desnick, RJ
    [J]. SCIENCE, 1996, 273 (5279) : 1236 - 1238
  • [7] MOLECULAR AND BIOLOGICAL CHARACTERIZATION OF A LIGAND FOR CD27 DEFINES A NEW FAMILY OF CYTOKINES WITH HOMOLOGY TO TUMOR-NECROSIS-FACTOR
    GOODWIN, RG
    ALDERSON, MR
    SMITH, CA
    ARMITAGE, RJ
    VANDENBOS, T
    JERZY, R
    TOUGH, TW
    SCHOENBORN, MA
    DAVISSMITH, T
    HENNEN, K
    FALK, B
    COSMAN, D
    BAKER, E
    SUTHERLAND, GR
    GRABSTEIN, KH
    FARRAH, T
    GIRI, JG
    PATRICIABECKMANN, M
    [J]. CELL, 1993, 73 (03) : 447 - 456
  • [8] Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization
    Gowen, M
    Lazner, F
    Dodds, R
    Kapadia, R
    Feild, J
    Tavaria, M
    Bertoncello, I
    Drake, F
    Zavarselk, S
    Tellis, I
    Hertzog, P
    Debouck, C
    Kola, I
    [J]. JOURNAL OF BONE AND MINERAL RESEARCH, 1999, 14 (10) : 1654 - 1663
  • [9] 4 STRUCTURALLY DISTINCT, NON-DNA-BINDING SUBUNITS OF HUMAN NUCLEAR RESPIRATORY FACTOR-2 SHARE A CONSERVED TRANSCRIPTIONAL ACTIVATION DOMAIN
    GUGNEJA, S
    VIRBASIUS, JV
    SCARPULLA, RC
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1995, 15 (01) : 102 - 111
  • [10] Hayman AR, 1996, DEVELOPMENT, V122, P3151