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ABSTRACT: Cell adhesion proteins that connect each cell to neighboring cells and the extracellular matrix play a fundamental role in metastasis. Mitogen-inducible gene-2 (MIG2), is a cell-matrix adhesion protein, which through migfilin, interacts with filamin-A, being linked to actin cytoskeleton. Aim: Recent studies have implicated both MIG2 and migfilin in cancer, but little is known regarding their expression in breast cancer. In this study, we investigated this topic.
mRNA and protein expression was examined in 30 breast cancer samples and compared to that of normal adjacent tissue using real time-polymerase chain reaction (PCR) and western blotting.
Our results showed that expression of MIG2 and migfilin was significantly reduced in the majority of the breast cancer tissues compared to normal tissues regardless of metastatic status and disease stage.
Both MIG2 and migfilin are down-regulated in breast cancer.
Anticancer research 05/2013; 33(5):1977-81. · 1.73 Impact Factor
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ABSTRACT: Osteoarthritis (OA) is a debilitating disease of the joints characterized by cartilage degradation but to date there is no available pharmacological treatment to inhibit disease progression neither is there any available biomarker to predict its development. In the present study, we examined the expression level and possible involvement of novel cell-ECM adhesion-related molecules such as Iintegrin Linked Kinase (ILK), PINCH, parvin, Mig-2 and Migfilin in OA pathogenesis using primary human articular chondrocytes from healthy individuals and OA patients. Our findings show that only ILK and Migfilin were upregulated in OA compared to the normal chondrocytes. Interestingly, Migfilin silencing in OA chondrocytes rather exacerbated than ameliorated the osteoarthritic phenotype, as it resulted in even higher levels of catabolic and hypertrophic markers while at the same time induced reduction in ECM molecules such as aggrecan. Furthermore, we also provide a link between Migfilin and β-catenin activation in OA chondrocytes, showing Migfilin to be inversely correlated with β-catenin. Thus, the present study emphasizes for the first time to our knowledge the role of Migfilin in OA and highlights the importance of cell-ECM adhesion proteins in OA pathogenesis.
Biochemical and Biophysical Research Communications 12/2012; · 2.48 Impact Factor
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ABSTRACT: INTRODUCTION: We aimed to explore the involvement of a multiallelic functional polymorphism in knee osteoarthritis (OA) susceptibility as a prototype of possible genetic factors escaping GWAS detection. METHODS: OA patients and controls from three European populations (Greece, Spain and the UK) adding up to 1003 patients (716 women, 287 men) that had undergone total knee joint replacement (TKR) due to severe primary OA and 1543 controls (758 women, 785 men) lacking clinical signs or symptoms of OA were genotyped for the D6S1276 microsatellite in intron 1 of BMP5. Genotype and mutiallelic trend tests were used to compare cases and controls. RESULTS: Significant association was found between the microsatellite and knee OA in women (P from 3.1 x10-4 to 4.1 x10-4 depending on the test), but not in men. Three of the alleles showed significant differences between patients and controls, one of them of increased risk and two of protection. The gender association and the allele direction of change were very concordant with the previously reported for hip OA. CONCLUSIONS: We have found association of knee OA in women with the D6S1276 functional microsatellite that modifies in cis the expression of BMP5 making this a sounder OA genetic factor and extending its involvement to other joint. This result also shows the interest of analysing other multiallelic polymorphisms.
Arthritis research & therapy 11/2012; 14(6):R257. · 4.27 Impact Factor
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ABSTRACT: Events normally taking place in the terminal chondrocyte differentiation in the growth plate are also observed during osteoarthritis (OA) development, suggesting that molecules, such as Wnts and bone morphogenetic proteins (BMPs) regulating chondrocyte activity in the growth plate, may play a key role in osteoarthritis pathogenesis. The aim of the study was to investigate the possible cross-talk between BMP-2 and Wnt/β-catenin pathways in OA progression.
Low-density-lipoprotein receptor-related protein 5 (LRP-5) and 6, BMP-2, -4, and -7, bone morphogenetic protein receptor-IA and IB (BMPR-IA and BMPR-IA), lymphoid enhancer factor-1 (LEF-1), and transcription factor 4 (TCF-4) expression levels were investigated in normal and osteoarthritic chondrocytes. LRP-5, β-catenin (phospho and active form), matrix metalloproteinases (MMPs) 7, 9, 13, 14, ADAMTS-4, 5, as well as collagen X (COL10A1) expression levels were evaluated after LRP-5 silencing in BMP-2-treated chondrocytes. The investigation of Smad1/5/8 binding to LRP-5 promoter was assessed with chromatin immunoprecipitation (ChIP). Furthermore, we evaluated the effect of experimental activation of the Wnt/β-catenin pathway with LiCl and LEF-1 silencing, in LiCl-treated chondrocytes, on matrix metalloproteinases (MMPs) 7, 9, 13, 14, ADAMTS-4, 5, and collagen X (COL10A1) expression, as well as possible interactions between LEF-1 and MMPs and COL10A1 promoters by using a ChIP assay.
LRP-5, BMP-2, BMP-4, BMPR-IA, and LEF-1 mRNA and protein expression levels were found to be significantly upregulated in osteoarthritic chondrocytes compared with normal. We showed that treatment of cultured chondrocytes with BMP-2 resulted in increased β-catenin nuclear translocation and LRP-5 expression and that the BMP-2-induced LRP-5 upregulation is mediated through Smad1/5/8 binding on LRP-5 promoter. LRP-5 silencing reduced nuclear β-catenin protein levels, MMPs and collagen X expression, whereas increased phospho-β-catenin protein levels in BMP-2-treated chondrocyte. Furthermore, we demonstrated that activation of the Wnt/β-catenin signaling pathway by LiCl and LEF-1 downregulation by using siRNA regulates MMP-9, 13, 14, ADAMTS-5, and COL10A1 expression, evidenced by the observed strong binding of LEF-1 to MMP-9, 13, 14, ADAMTS-5 and COL10A promoters.
Our findings suggest, for the first time to our knowledge, that BMP-2-induced Wnt/β-catenin signaling activation through LRP-5 may contribute to chondrocyte hypertrophy and cartilage degradation in osteoarthritis.
Arthritis research & therapy 04/2012; 14(2):R82. · 4.27 Impact Factor
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ABSTRACT: Hypertrophy and impaired mineralization are two processes closely associated with osteoarthritis (OA). 1,25-dihydroxyvitamin D(3) (1a,25(OH)(2)D(3)) and inorganic phosphate (Pi) are two important factors that are implicated in calcium and phosphate homeostasis of bone metabolism and both can be regulated by the circulating phosphaturic factor fibroblast growth factor 23 (FGF23). The objective of this study was to investigate the role of 1a,25(OH)(2)D(3) and Pi and the molecular mechanism through which they contribute to hypertrophy and mineralization in human osteoarthritic chondrocytes. For this purpose, primary human chondrocytes were obtained from articular cartilage which was collected after total knee replacement surgery in OA patients. FGF23, fibroblast growth factor receptor 1c (FGFR1c), vitamin D(3) receptor (VDR), and phosphate inorganic transporter-1 and -2 (PiT-1 and PiT-2) expression levels were evaluated and found to be significantly higher in OA chondrocytes compared with normal. In addition, we observed that the binding of FGF23 to FGFR1c was stronger in OA chondrocytes compared with normal. Chromatin immunoprecipitation (ChIP) assay revealed, for the first time, the presence of two vitamin D response elements (VDREs) in the FGF23 promoter. Treatment of normal chondrocytes with 1a,25(OH)(2)D(3) or Pi resulted in significant up-regulation of VDR, FGF23, PiT-1, PiT-2 mRNA and protein levels, extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation and induction of hypertrophy markers collagen type X (COL10A1), osteopontin (OPN), osteocalcin (OC), catabolic markers metalloproteinase-13 (MMP-13) and the apoptotic marker caspase-9. Furthermore, VDR silencing in OA chondrocytes negatively regulated FGF23, COL10A1, OPN, OC, MMP-13 and caspase-9 expressions and ERK1/2 phosphorylation. Finally, combined VDR silencing and PiT-1, PiT-2 inhibition in OA chondrocytes resulted in additive down-regulation of FGF23 expression, ERK1/2 activation and COL10A1, OPN, OC, MMP-13 and caspase-9 expression levels. We propose that 1a,25(OH)(2)D(3) and Pi act synergistically through FGF23 signaling and ERK1/2 phosphorylation contributing to late hypertrophic events and impaired mineralization in osteoarthritic chondrocytes.
Experimental Biology and Medicine 03/2012; 237(3):241-53. · 2.64 Impact Factor
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Masahiro Nakajima,
Dongquan Shi,
Jin Dai, Aspasia Tsezou,
Minghao Zheng,
Paul E Norman,
Ching-Heng Chou,
Ming Ta Michael Lee,
Joo-Yeon Hwang,
Dong-Hyun Kim,
Atsushi Takahashi,
Shiro Ikegawa,
Qing Jiang
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ABSTRACT: Osteoarthritis (OA) is a common disease with a genetic component for its etiology. Recently, a genetic association of a single nucleotide polymorphism (SNP), rs17039192 in HIF-2α with knee OA has been reported in a Japanese population; however, controversy exits for its replication and a role of HIF-2α in OA. This study aimed to evaluate the association of the SNP by a large-scale replication study. A total of 8,457 subjects (3,129 OA cases and 5,328 controls) from seven independent cohorts from six countries (Japan, China, Taiwan, Korea, Greece, and Australia) were recruited and genotyped. The association of rs17039192 with knee OA was evaluated by meta-analyses. The association of the HIF-2α SNP was not replicated in any of the populations. Contrary to the previous report, the odds ratios (ORs) of the risk allele frequency were all less than 1. A combined analysis for the seven populations also showed no replication of the association (OR = 0.91, 95% confidence interval = 0.81-1.03). Our large-scale meta-analysis showed that the association of rs17039192 in HIF-2α with knee OA is negative. The significance of HIF-2α in human OA (idiopathic OA as a common disease) should be further evaluated carefully.
Journal of Orthopaedic Research 01/2012; 30(8):1244-8. · 2.81 Impact Factor
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ABSTRACT: Recent studies have implied that osteoarthritis (OA) is a metabolic disease linked to deregulation of genes involved in lipid metabolism and cholesterol efflux. Sterol Regulatory Element Binding Proteins (SREBPs) are transcription factors regulating lipid metabolism with so far no association with OA. Our aim was to test the hypothesis that SREBP-2, a gene that plays a key role in cholesterol homeostasis, is crucially involved in OA pathogenesis and to identify possible mechanisms of action.
We performed a genetic association analysis using a cohort of 1,410 Greek OA patients and healthy controls and found significant association between single nucleotide polymorphism (SNP) 1784G>C in SREBP-2 gene and OA development. Moreover, the above SNP was functionally active, as normal chondrocytes' transfection with SREBP-2-G/C plasmid resulted in interleukin-1β and metalloproteinase-13 (MMP-13) upregulation. We also evaluated SREBP-2, its target gene 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR), phospho-phosphoinositide3-kinase (PI3K), phospho-Akt, integrin-alphaV (ITGAV) and transforming growth factor-β (TGF-β) mRNA and protein expression levels in osteoarthritic and normal chondrocytes and found that they were all significantly elevated in OA chondrocytes. To test whether TGF-β alone can induce SREBP-2, we treated normal chondrocytes with TGF-β and found significant upregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13. We also showed that TGF-β activated aggrecan (ACAN) in chondrocytes only through Smad3, which interacts with SREBP-2. Finally, we examined the effect of an integrin inhibitor, cyclo-RGDFV peptide, on osteoarthritic chondrocytes, and found that it resulted in significant upregulation of ACAN and downregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13 expression levels.
We demonstrated, for the first time, the association of SREBP-2 with OA pathogenesis and provided evidence on the molecular mechanism involved. We suggest that TGF-β induces SREBP-2 pathway activation through ITGAV and PI3K playing a key role in OA and that integrin blockage may be a potential molecular target for OA treatment.
PLoS ONE 01/2012; 7(5):e35753. · 4.09 Impact Factor
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ABSTRACT: Radiotherapy is an important treatment modality against cancer resulting in apoptosis and inhibition of cell growth. Survivin is an important cancer biomarker conferring to tumour cells increased survival potential by inhibiting apoptosis. In the present study, we investigated the implication of breast cancer cells features, as hormone receptors and p53 status, in the radio-resistance of breast cancer cells and in the regulation of survivin's expression by nuclear factor (NF)-κB and c-myc. Six breast cancer cell lines Michigan Cancer Foundation (MCF-7), MCF-7/Human Epidermal Growth Factor Receptor (HER)2, M. D. Anderson - Metastatic Breast (MDA-MB-231), SK-BR-3, BT-474 and Human Breast Lactating (HBL-100) were irradiated and cell viability as well as cell cycle distribution were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Survivin mRNA and protein levels were evaluated by real time PCR and Western blot analysis. Survivin and HER2 gene knockdown was performed with siRNA technology and investigation of transcription factors binding to survivin and c-myc gene promoters was assessed by chromatin immunoprecipitation. Student's t-test and F-statistics were used for statistical evaluation. Our results demonstrated that only HER2(+) breast cancer cells up-regulated survivin upon irradiation, whereas HER2 knockdown in HER2(+) cells led to survivin's down-regulation. Survivin and especially HER2 knockdown abolished the observed G2/M cell cycle checkpoint and reduced the radio-resistance of HER2 overexpressing breast cancer cells. Additionally, HER2 was found to regulate survivin's expression through NF-κB and c-myc transcription factors. This study revealed the significance of HER2 in the radio-resistance of HER2(+) breast cancer cells through induction of transcription factors NF-κB and c-myc, leading to activation of survivin, a downstream target oncogene preventing apoptosis.
Journal of Cellular and Molecular Medicine 07/2011; 15(7):1542-50. · 4.13 Impact Factor
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ABSTRACT: Telomerase activity (TA), frequently observed in cancer, compensates for telomere shortening thus preventing cell senescence and conferring resistance to therapy. In the present study, we investigated the expression of human telomerase reverse transcriptase (hTERT) and TA and their regulation, as well as apoptotic rates and correlation with the presence of human epidermal growth factor receptor 2 (HER2), in irradiated tumour-derived breast cancer cells.
In 50 breast cancer tissue samples hTERT mRNA expression and TA were correlated with cell features (HER2, Estrogen and Progesterone Receptor status). Cells from six samples were then irradiated with 10 and 20 Gy; apoptotic rates were measured by flow cytometry, hTERT mRNA expression by real-time polymerase chain reaction and TA by telomeric repeat amplification protocol assay, at 24-144 h post-irradiation. Chromatin immunoprecipitation was performed to investigate hTERT and cellular-myelocytomatosis (c-myc) promoters' activity. HER2 gene knockdown was performed using small interfering RNA technology.
hTERT/TA were found increased only in irradiated HER2-positive cells, which were found to be more radioresistant, while HER2 knockdown led to hTERT/TA downregulation. HER2 was found to mediate hTERT expression through activation of Nuclear Factor-kappa B (NF-κB) and c-myc.
The present study suggests that following irradiation, HER2 receptor activates hTERT/telomerase, increasing the breast cancer cells' survival potential, through sequential induction of transcription factors NF-κΒ and c-myc.
International Journal of Radiation Biology 06/2011; 87(6):609-21. · 2.28 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) are involved in mediating cell activation on stimulation with microbial components. Our objective was to investigate the role of TLR-2 mediated by the NF-κB pathway in septic arthritic chondrocytes. TLR-1, -2, and -6 mRNA expression levels were investigated in septic and normal chondrocytes using real-time reverse transcription-PCR. TLR-2 and MMP-13 mRNA and protein levels were measured using real-time PCR and Western blot analysis, respectively. Blocking TLR-2 mRNA expression was performed using small interfering RNA (siRNA) against TLR-2 and subsequently MMP-3, MMP-13, IL-1β, and IL-6 mRNA levels, as well as p65 NF-κB, IkBα, and MMP-13 protein levels were evaluated using real-time PCR and Western blot analysis. IL-6 protein levels were measured using ELISA assay. We observed that TLR-1, -2, and -6 mRNA expression levels were significantly higher in septic compared to normal chondrocytes. MMP-13 mRNA and protein expressions were also significantly upregulated in septic arthritic cartilage. Blocking TLR-2 mRNA expression in septic chondrocytes resulted in significant increase of inactivated nonphosphorylated p65 NF-κB and IkBα protein levels and reduction in MMP-13, IL-1β, and IL-6 expression. Our findings suggest the pro-inflammatory and catabolic role of TLR-2 mediated by the NF-κB pathway in septic arthritis. Modulation of TLR-mediated signaling may be a potential therapeutic strategy for the prevention of postinfectious cartilage degradation in articular joints.
Journal of Orthopaedic Research 02/2011; 29(2):247-51. · 2.81 Impact Factor
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Nature medicine 01/2011; 17(1):26-7; author reply 27-9. · 27.14 Impact Factor
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Ingrid Meulenbelt,
Steffan D Bos,
Kay Chapman,
Ruud van der Breggen,
Jeanine J Houwing-Duistermaat,
Dennis Kremer,
Margreet Kloppenburg,
Andrew Carr, Aspasia Tsezou,
Antonio González,
John Loughlin,
P Eline Slagboom
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ABSTRACT: To study whether common genetic variants of the genes involved in the complex regulatory mechanism determining the intracellular bio-availability of T3 influence osteoarthritis onset.
In total 17 genetic variants within the genes encoding WD40-repeat/SOCS-box protein 1, ubiquitin specific protease 33, thyroid hormone receptor α, deiodinase, iodothyronine, type III (DIO3) and Indian hedgehog were measured and associated with osteoarthritis in a meta-analyses in European populations from the UK, The Netherlands, Greece and Spain containing a total of 3252 osteoarthritis cases and 2132 controls.
The minor allele of the DIO3 variant rs945006 showed suggestive evidence for protective association in the overall meta-analyses, which was supported by individual osteoarthritis studies and osteoarthritis subtypes. The association appeared most significant in cases with knee and/or hip with an allelic OR of 0.81 (95% CI 0.70 to 0.930) with a nominal p value of 0.004 and a permutation-based corrected p value for multiple testing of 0.039.
The findings suggest that the DIO3 gene modulates osteoarthritis disease risk; however, additional studies are necessary to replicate our findings. To elucidate the molecular mechanisms focus should be on the local adaptation to T3 availability either during the endochondral ossification process or during ageing of the articular cartilage.
Annals of the rheumatic diseases 01/2011; 70(1):164-7. · 8.11 Impact Factor
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ABSTRACT: Although leptin has been found to be implicated in obesity-related breast carcinogenesis in postmenopausal women, the molecular mechanisms involved are yet to be defined. Recently, the antiapoptotic gene survivin has been recognized as a target gene for leptin in breast cancer. The aim of this study was to investigate the effect of leptin on the expression of survivin and on the transcriptional activity of its promoter in MCF-7 breast cancer cells. We also studied the potential involvement of SOCS-3 (a negative regulator of leptin's main signaling pathway JAK2/STAT3) in the expression of leptin-mediated survivin. Our results showed a significant increase in the mRNA (dose-dependent increase of 40-70%) and protein expression levels of survivin 24 h post-leptin treatment, which was followed by a significant decrease at 48 and 72 h (of 60-70%). In accordance, a chromatin immunoprecipitation assay revealed an initial strong binding of STAT3 to the survivin promoter, which was no longer detected after 24 h. Myc/mad/max network proteins and histone H3 acetylation status were not found to contribute to the expression of leptin-mediated survivin. Furthermore, a protein immunoprecipitation assay detected an enhanced SOCS-3 binding to the long isoform of leptin's receptor (Ob-Rb) 48 and 72 h after leptin administration, thus conferring inhibition to leptin signaling. In conclusion, our findings suggest, for the first time to our knowledge, that the effect of leptin on the antiapoptotic gene survivin is limited by the inhibitory role of SOCS-3 in the leptin-activated JAK2/STAT3 signaling pathway in MCF-7 breast cancer cells.
Experimental Biology and Medicine 01/2011; 236(1):70-6. · 2.64 Impact Factor
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ABSTRACT: We assessed the association between (CA)n repeat polymorphism of angiotensinogen (AGT), 250 base pair (bp) insertion/deletion (I/D) of angiotensin-converting enzyme (ACE), tetranucleotide repeat polymorphism (TCTG)n of renin (REN), (CT)n repeat polymorphism of the natriuretic peptide receptor A (NPRA) genes, and the presence and extent of coronary artery disease (CAD) in Greek patients with a history of myocardial infarction (MI). A total of 158 post-MI patients referred for coronary angiography were compared with 144 controls. The SS genotype of the AGT gene was related with an increased risk for 3-vessel CAD (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.05-3.61; P = .041), whereas the SL genotype was related with a decreased risk (OR, 0.44; 95% CI, 0.22-0.87; P = .019). Moreover, there was a trend for the SL genotype of the REN gene toward increased risk for CAD. There was a significant association between (CA)n polymorphism of the AGT gene and the extent of CAD in Greek patients with a history of MI.
Angiology 11/2010; 61(8):737-43. · 1.51 Impact Factor
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Evangelos Evangelou,
Ana M Valdes,
Hanneke J M Kerkhof,
Unnur Styrkarsdottir,
Yanyan Zhu,
Ingrid Meulenbelt,
Rik J Lories,
Fotini B Karassa,
Przemko Tylzanowski,
Steffan D Bos, [......],
Eleftheria Zeggini,
Guangju Zhai,
Feng Zhang,
Ingileif Jonsdottir,
Andre G Uitterlinden,
David T Felson,
Joyce B van Meurs,
Kari Stefansson,
John P A Ioannidis,
Timothy D Spector
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ABSTRACT: Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component.
A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets.
With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 × 10⁻⁹), thereby confirming its role as a susceptibility locus for OA.
The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, β), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
Annals of the rheumatic diseases 11/2010; 70(2):349-55. · 8.11 Impact Factor
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H J M Kerkhof,
I Meulenbelt,
T Akune,
N K Arden,
A Aromaa,
S M A Bierma-Zeinstra,
A Carr,
C Cooper,
J Dai,
M Doherty, [......],
A Sudo,
A Tamm,
A E Tamm, A Tsezou,
A Uchida,
A G Uitterlinden,
J M Wilkinson,
N Yoshimura,
A M Valdes,
J B J van Meurs
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ABSTRACT: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P =0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3×10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small.
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
Osteoarthritis and Cartilage 11/2010; 19(3):254-64. · 3.90 Impact Factor
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Hanneke J M Kerkhof,
Ingrid Meulenbelt,
Andrew Carr,
Antonio Gonzalez,
Deborah Hart,
Albert Hofman,
Margreet Kloppenburg,
Nancy E Lane,
John Loughlin,
Michael C Nevitt,
Huibert A P Pols,
Fernando Rivadeneira,
Eline P Slagboom,
Tim D Spector,
Lisette Stolk, Aspasia Tsezou,
André G Uitterlinden,
Ana M Valdes,
Joyce B J van Meurs
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ABSTRACT: The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis.
In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls.
The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05).
This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.
BMC Medical Genetics 11/2010; 11:164. · 2.33 Impact Factor
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ABSTRACT: Osteoarthritis (OA) is an age-related degenerative disease comprising the main reason of handicap in the Western world. Interestingly, to date, there are neither available biomarkers for early diagnosis of the disease nor any effective therapy other than symptomatic treatment and joint replacement surgery. OA has long been associated with obesity, mainly due to mechanical overload exerted on the joints. Recent studies however, point to the direction that OA is a metabolic disease, as it also involves non-weight bearing joints. In fact, altered lipid metabolism may be the underlying cause. First, adipokines have been shown to be key regulators of OA pathogenesis. Second, epidemiological studies have shown serum cholesterol to be a risk factor for OA development. Third, lipid deposition in the joint is observed at the early stages of OA before the occurrence of histological changes. Fourth, proteomic analyses have shown an important connection between OA and lipid metabolism. Finally, recent gene expression studies reveal a deregulation of cholesterol influx and efflux and in the expression of lipid metabolism-related genes. Interestingly, lipids and lipid metabolism are known to be implicated in the development and progression of another age-related degenerative disease, atherosclerosis (ATH). Thus, although it is tempting to speculate that the osteoarthritic chondrocyte has been transformed to foam cell, it has not been proven yet. However, this may be an intriguing theory linking ATH and OA, which may open new avenues to novel therapeutic interventions for OA taking advantage of previous knowledge from ATH.
Progress in lipid research 11/2010; 50(2):133-40. · 10.67 Impact Factor
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ABSTRACT: Previous studies have suggested that leptin works as a key regulator in the pathogenesis of osteoarthritis (OA), and genetic factors modulate OA. This study assessed the contribution of leptin gene (LEP) polymorphism(s) to knee OA among Han Chinese. Three tag single-nucleotide polymorphisms (SNPs) covering all those LEP SNPs of which the minor allele frequencies were over 10% were selected. Study subjects (697 patients and 699 controls) were divided into four groups (underweight, normal weight, overweight and obese) by body mass index (BMI). Allele and genotype frequencies in the three tag SNPs were significantly different in the normal weight and overweight groups. In the normal weight, overweight and obese groups, BMI (P=4.3 × 10(-5), 0.012 and 0.009, respectively) and gender (P=3.5 × 10(-22), 5.1 × 10(-23) and 2.1 × 10(-8), respectively) were effective factors. Age was an independent effective factor in the overweight group (P=0.009). Haplotypes were associated with OA in the normal weight group (CAT, P=0.015) and the overweight group (AGC, P=0.015). Our results suggest an association between LEP and knee OA in the normal weight and overweight groups among Han Chinese.
Journal of Human Genetics 10/2010; 55(10):704-6. · 2.57 Impact Factor
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ABSTRACT: Osteoarthritis (OA) is characterized by irreversible destruction of the articular cartilage. OA affects more than 100 million individuals worldwide and has a major impact on patients' quality of life. The lack of effective therapy that prevents, inhibits or reverses the progress of OA often leaves only the option of surgical interventions. Thus, identification of the factors that contribute to OA pathogenesis is necessary for better understanding of OA pathobiology and discovery of effective therapies. Recent proteomic studies have been conducted to identify pathological mediators and biomarkers of OA, which have pinpointed novel pathways involved in cartilage degeneration. This article summarizes the recent findings, compares major techniques used in OA proteomics and discusses key proteins in OA and their potential use as therapeutic targets.
Expert Review of Proteomics 10/2010; 7(5):749-60. · 3.68 Impact Factor
