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ABSTRACT: Osteoclasts are bone-resorbing cells differentiated from macrophage/monocyte lineage precursors upon receptor activator of NF-κB ligand (RANKL) stimulation. In a proteomic approach to identify proteins involved in osteoclastogenesis, we observed a dramatic increase in the expression of neurite outgrowth inhibitor A (Nogo-A) upon RANKL stimulation of mouse bone marrow macrophages (BMMs) in a nuclear factor of activated T cell cytoplasmic 1 (NFATc1)-dependent manner. The knockdown of Nogo-A in BMMs significantly reduced RANKL-dependent osteoclast differentiation accompanied by diminished NFATc1 induction, suggesting that a positive feedback mechanism is involved. Conversely, Nogo-A overexpression in BMMs as well as in RAW264.7 macrophages greatly augmented osteoclastogenesis, with concomitant increase in the NFATc1 induction. Both the mitogen-activated protein kinase (MAPK) pathway and calcium oscillation, which are central to RANKL-dependent NFATc1 activation and induction, were enhanced by Nogo-A. Finally, Nogo-A knockdown in mouse calvariae prevented interleukin 1 (IL-1)-induced bone loss. These findings not only reveal an unprecedented extraneural role of Nogo-A in osteoclastogenesis but also suggest a novel drug target against bone-lytic diseases.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2012; 27(5):1043-54. · 6.04 Impact Factor
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Cheol-Kyu Park,
Tae-Jong Kim,
Young-Nan Cho,
Il-Soo Kim,
Ho-Jun Lee,
Kyung-Eun Lee,
Seong-Chang Park,
Jong-Sun Kim,
Dong-Jin Park,
Sung-Ji Lee,
Seong-Rye Seo,
Jeong-Chul Kim,
Sang-Gook Song,
Shin-Seok Lee,
Yong-Wook Park
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ABSTRACT: Rheumatoid arthritis (RA) and antisynthetase syndrome (ASS) are distinct clinical syndromes, and their co-occurrence is rarely encountered. The authors report the case of a 56-year-old female patient with RA of 3 years duration who suddenly developed ASS, and include a review of the literature. The patient was diagnosed with ASS based on; positivity for anti-histidyl-tRNA synthetase (Jo-1) antibody, interstitial lung disease, polyarthritis, and mechanic's hands. High-dose corticosteroid and pulse intravenous cyclophosphamide were used to control the ASS. This case demonstrates that ASS should be considered during clinical presentations due to its potential overlap with RA.
Rheumatology International 10/2009; 31(4):529-32. · 1.88 Impact Factor
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ABSTRACT: Invariant natural killer T (iNKT) cells have been reported to play a role in the pathogenesis of murine asthma. However, the role for iNKT cells in the pathogenesis of human asthma is not defined. In this study we aimed to determined how blood iNKT cells are associated with atopy in asthmatic individuals. Peripheral blood mononuclear cells were isolated from 45 asthmatic subjects. iNKT cells were stained with 6B11 mAb, anti-TCRvalpha24 mAb, or alpha-galactosylceramide (GalCer)-loaded CD1d- tetramer and analyzed with flow-cytometric assays. Increased serum total IgE or one or more positive skin reactions to common allergens were used as atopic indexes. Asthmatic subjects with IgE > 500 IU/ml showed lower frequency of CD4(+) 6B11(+) iNKT cells (p < 0.01) or CD4(+) Valpha24(+) iNKT cells (p < 0.01) compared with subjects with IgE < or = 500 IU/ml. Asthmatic subjects with atopy on skin tests had lower frequency of CD4(+) alpha-GalCer-loaded CD1d- tetramer(+) iNKT cells compared with those without atopy (p < 0.05). The frequency of CD4(+) Valpha24(+) iNKT cells was negatively correlated with total IgE in asthmatic subjects (r = -0.33, p < 0.05). In summary, blood CD4(+) iNKT cells were inversely associated with atopic indexes in asthmatic individuals. We hypothesize that blood CD4(+) iNKT cells might behave like T(h)1-like iNKT cells in human asthma.
Human immunology 10/2009; 71(2):186-91. · 2.55 Impact Factor
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ABSTRACT: Osteoclasts are cells that have a specialized role for bone resorption and are responsible for many bone diseases such as osteoporosis. As herbal products are invaluable sources in discovery of compounds for new therapies, we sought to identify compounds efficacious in suppressing osteoclastogenesis from medicinal plants that have been implicated for treatment of osteoporotic conditions. Bavachalcone was isolated from Psoralea corylifolia, and its effects on osteoclast differentiation were evaluated with primary cultures of osteoclast precursor cells. In addition, the molecular mechanism of action was investigated. Bavachalcone inhibited osteoclast formation from precursor cells with the IC(50) of approximately 1.5 microg ml(-1). The activation of MEK, ERK, and Akt by receptor activator of nuclear factor kappaB ligand (RANKL), the osteoclast differentiation factor, was prominently reduced in the presence of bavachalcone. The induction of c-Fos and NFATc1, key transcription factors for osteoclastogenesis, by RANKL was also suppressed by bavachalcone. In conclusion, bavachalcone inhibits osteoclastogenesis by interfering with the ERK and Akt signaling pathways and the induction of c-Fos and NFATc1 during differentiation. Our results suggest that bavachalcone may be useful as a therapeutic drug for bone resorption-associated diseases.
Biochemical pharmacology 07/2008; 75(11):2175-82. · 4.25 Impact Factor
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Cheol Kyu Park,
Hyung Joon Kim,
Han Bok Kwak,
Tae Hoon Lee,
Myun-Ho Bang,
Chul Min Kim,
Youngkyun Lee,
Dae Kyun Chung,
Nam-In Baek,
Jiyoung Kim,
Zang Hee Lee,
Hong-Hee Kim
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ABSTRACT: Osteoclasts are responsible for bone lysis in several bone diseases such as osteoporosis and rheumatoid arthritis. Natural products from plants have been invaluable source in discovery of compounds for new therapies. In this study, we screened plant products for potential application to therapy for bone loss using a primary osteoclastogenesis culture system and found that extract of Stewartia koreana (SKE) had a strong inhibitory effect on osteoclast formation. To gain molecular insights, we examined the effect of SKE on signaling pathways and transcription factors stimulated by the osteoclast differentiation factor RANKL. SKE suppressed the induction of c-Fos and NFATc1 by RANKL. However, SKE did not inhibit NF-kappaB activation by RANKL. Among the MAPKs stimulated by RANKL, SKE significantly reduced the activation of ERK and p38. Therefore, the anti-osteoclastogenic effect of SKE is likely to be elicited by interference with RANKL signaling to ERK and p38, which mediate the induction of c-Fos and subsequently that of NFATc1. Consistent with the in vitro effect on osteoclast differentiation, SKE showed a great inhibitory effect on in vivo bone loss in LPS-challenged mice. Taken together, we demonstrated that SKE has inhibitory effects on osteoclast differentiation in vitro and confirmed its in vivo efficacy in prevention of inflammatory bone loss.
International Immunopharmacology 01/2008; 7(12):1507-16. · 2.38 Impact Factor
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ABSTRACT: In inflammatory responses, induction of cytokines and other immune regulator genes in macrophages by pathogen-associated signal such as lipopolysaccharide (LPS) plays a crucial role. In this study, the gene expression profile changes by LPS treatment in the macrophage/monocyte lineage cell line RAW264.7 was investigated. A 60-mer oligonucleotide microarray of which probes target 32381 mouse genes was used. A reverse transcription-in vitro translation labeling protocol and a chemileuminescence detection system were employed. The mRNA expression levels in RAW264.7 cells treated for 6 h with LPS and the control vehicle were compared. 747 genes were up-regulated and 523 genes were down-regulated by more than 2 folds. 320 genes showing more than 4-fold change by LPS treatment were further classified for the biological process, molecular function, and signaling pathway. The biological process categories that showed high number of increased genes include the immunity and defense, the nucleic acid metabolism, the protein metabolism and modification, and the signal transduction process. The chemokine-cytokine signaling, interleukin signaling, Toll receptor signaling, and apoptosis signaling pathways involved high number of genes differentially expressed in response to LPS. These expression profile data provide more comprehensive information on LPS-target genes in RAW264.7 cells, which will be useful in comparing gene expression changes induced by extracts and compounds from anti-inflammatory medicinal herbs.
Archives of Pharmacal Research 11/2006; 29(10):890-7. · 1.59 Impact Factor
