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1.  An Association Study between Hypoxia Inducible Factor-1alpha (HIF-1α) Polymorphisms and Osteonecrosis 
PLoS ONE  2013;8(11):e79647.
Bone hypoxia resulting from impaired blood flow is the final pathway for the development of osteonecrosis (ON). The aim of this study was to evaluate if HIF-1α, the major transcription factor triggered by hypoxia, is genetically implicated in susceptibility to ON. For this we analyzed frequencies of three known HIF-1α polymorphisms: one in exon 2 (C111A) and two in exon 12 (C1772T and G1790A) and their association with ON in a Greek population. Genotype analysis was performed using PCR-RFLP and rare alleles were further confirmed with sequencing. We found that genotype and allele frequency of C1772T and G1790A SNP of HIF-1α (SNPs found in our cohort) were not significantly different in ON patients compared to control patients. Furthermore these SNPs could not be associated with the different subgroups of ON. At the protein level we observed that the corresponding mutations (P582S and A588T, respectively) are not significant for protein function since the activity, expression and localization of the mutant proteins is practically indistinguishable from wt in HEK293 and Saos-2 cells. These results suggest that these missense mutations in the HIF-1α gene are not important for the risk of developing ON.
doi:10.1371/journal.pone.0079647
PMCID: PMC3832621  PMID: 24260273
2.  Daptomycin use in patients with osteomyelitis: a preliminary report from the EU-CORESM database 
Background
Osteomyelitis is a complex and heterogeneous group of infections that require surgical and antimicrobial interventions. Because treatment failure or intolerance is common, new treatment options are needed. Daptomycin has broad Gram-positive activity, penetrates bone effectively and has bactericidal activity within biofilms. This is the first report on clinical outcomes in patients with osteomyelitis from the multicentre, retrospective, non-interventional European Cubicin® Outcomes Registry and Experience (EU-CORESM), a large database on real-world daptomycin use.
Patients and methods
In total, 220 patients were treated for osteomyelitis; the population was predominantly elderly, with predisposing baseline conditions such as diabetes and chronic renal/cardiac diseases.
Results
Most patients (76%) received prior antibiotic treatment, and first-line treatment failure was the most frequent reason to start daptomycin. Common sites of infection were the knee (22%) or hip (21%), and the most frequently isolated pathogens were Staphylococcus aureus (33%) and coagulase-negative staphylococci (32%). Overall, 52% of patients had surgery, 55% received concomitant antibiotics and 29% received a proportion of daptomycin therapy as outpatients. Clinical success was achieved in 75% of patients. Among patients with prosthetic device-related osteomyelitis, there was a trend towards higher success rates if the device was removed. Daptomycin was generally well tolerated.
Conclusions
This analysis suggests that daptomycin is an effective and well-tolerated treatment option for osteomyelitis and highlights the importance of optimal surgical intervention and appropriate microbiological diagnosis for clinical outcomes.
doi:10.1093/jac/dkt067
PMCID: PMC3682689  PMID: 23515247
lipopeptides; Gram-positive infections; bone infections; prosthetic device infections; non-interventional study
3.  Cumulative keyboard strokes: a possible risk factor for carpal tunnel syndrome 
Background
Contradictory reports have been published regarding the association of Carpal Tunnel Syndrome (CTS) and the use of computer keyboard. Previous studies did not take into account the cumulative exposure to keyboard strokes among computer workers. The aim of the present study was to investigate the association between cumulative keyboard use (keyboard strokes) and CTS.
Methods
Employees (461) from a Governmental data entry & processing unit agreed to participate (response rate: 84.1 %) in a cross-sectional study. Α questionnaire was distributed to the participants to obtain information on socio-demographics and risk factors for CTS. The participants were examined for signs and symptoms related to CTS and were asked if they had previous history or surgery for CTS. The cumulative amount of the keyboard strokes per worker per year was calculated by the use of payroll’s registry. Two case definitions for CTS were used. The first included subjects with personal history/surgery for CTS while the second included subjects that belonged to the first case definition plus those participants were identified through clinical examination.
Results
Multivariate analysis used for both case definitions, indicated that those employees with high cumulative exposure to keyboard strokes were at increased risk of CTS (case definition A: OR = 2.23;95 % CI = 1.09-4.52 and case definition B: OR = 2.41; 95%CI = 1.36-4.25). A dose response pattern between cumulative exposure to keyboard strokes and CTS has been revealed (p < 0.001).
Conclusions
The present study indicated a possible association between cumulative exposure to keyboard strokes and development of CTS. Cumulative exposure to key-board strokes would be taken into account as an exposure indicator regarding exposure assessment of computer workers. Further research is needed in order to test the results of the current study and assess causality between cumulative keyboard strokes and development of CT.
doi:10.1186/1745-6673-7-16
PMCID: PMC3480831  PMID: 22856674
4.  Factors affecting the quality of life after total knee arthroplasties: a prospective study 
Background
The purpose of the study is to evaluate the self-reported outcomes in the first year after primary total knee arthroplasty (TKA), and to determine factors influencing the quality of life (QoL) 6 weeks, 3, 6, and 12 months after TKA.
Methods
A cohort of patients with knee osteoarthritis undergoing primary TKA at two hospitals (a regional university hospital and a capital’s metropolitan hospital) was prospectively followed for 12 months. Patients were assessed preoperatively and at 4 postoperative time-points, with the use of self-reported measurements for pain, physical function and depression with the following evaluation tools: Western Ontario and McMaster Osteoarthritis Index [WOMAC], Knee Society Scoring system [KSS], Centre for Epidemiological Studies Depression Scale, [CES-D10] and visual analog scale [VAS] for pain). General linear modelling for repeated measures was used to evaluate the effect of each independent variable including clinical and sociodemographic data. Differences between groups at different time points were tested by the independent samples t-test.
Results
Of the 224 eligible patients, 204 (162 females, mean age 69.2) were included in the analysis. Response rate at one year was 90%. At 6 weeks after surgery, despite improvement in pain and alleviation of the depressive mood, the physical function remained less satisfactory. Females presented lower scores in terms of quality of life, both preoperatively and 6 weeks after TKA. Significant improvement was already experienced at 3 months postoperatively. According to WOMAC, KSS, CES-D10 and pain VAS scores the Qol was significantly improved 12 months after TKA (P < 0.001). CES-D10 score was positively correlated with WOMAC and pain VAS scores at all the time points assessed (P < 0.001). Age, body mass index (BMI), place of residence, level of education and social support were not significant predictors of QoL after TKA.
Conclusions
Patients experienced great improvement in their QoL after TKA in spite of a less satisfactory physical function in the first 6 weeks after surgery, with noticeable differences in the QoL among genders in the same time period. After that period all patients experienced significant improvement for all the measured parameters, until the third postoperative month with smaller changes thereafter.
doi:10.1186/1471-2474-13-116
PMCID: PMC3476961  PMID: 22748117
Total knee arthroplasty; Quality of life; Osteoarthritis; Rehabilitation
5.  Central Role of SREBP-2 in the Pathogenesis of Osteoarthritis 
PLoS ONE  2012;7(5):e35753.
Background
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.
Methodology/Principal Findings
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.
Conclusions/Significance
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.
doi:10.1371/journal.pone.0035753
PMCID: PMC3360703  PMID: 22662110
6.  Bone morphogenetic protein-2-induced Wnt/β-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/ar3805
PMCID: PMC3446456  PMID: 22513174
7.  Reconstruction nailing for ipsilateral femoral neck and shaft fractures 
The surgical management of ipsilateral fractures of the femoral neck and shaft presents a difficult and challenging problem for the orthopaedic surgeon. The purpose of the present study was to report the mid-term results and complications in a series of patients who sustained ipsilateral femoral neck and shaft fractures and treated in our trauma department with a single reconstruction nail for both fractures. Eleven patients were included in the study with an average age of 46.4 years. The mean follow-up was 47 months (range, 15–75 months). There were no cases of a missed diagnosis at initial presentation. The mean time to union was 4.5 months for the neck fracture and 8.2 months for the shaft. There were no cases of avascular necrosis of the femoral head or non-union of the neck fracture. The mean Harris Hip Score was (85 ± 4.3). Complications included two cases of shaft fracture non-union and one case of peroneal nerve palsy. Heterotopic ossification at the tip of the greater trochanter was evident in two cases without causing any functional deficit. The current study suggests that reconstruction nailing produces satisfactory clinical and functional results in the mid-term. The complications involved only the femoral shaft fracture and were successfully treated with a single operative procedure.
doi:10.1007/s11751-011-0117-0
PMCID: PMC3150652  PMID: 21779894
Femoral shaft fractures; Ipsilateral hip; Reconstruction nail
8.  Reconstruction nailing for ipsilateral femoral neck and shaft fractures 
The surgical management of ipsilateral fractures of the femoral neck and shaft presents a difficult and challenging problem for the orthopaedic surgeon. The purpose of the present study was to report the mid-term results and complications in a series of patients who sustained ipsilateral femoral neck and shaft fractures and treated in our trauma department with a single reconstruction nail for both fractures. Eleven patients were included in the study with an average age of 46.4 years. The mean follow-up was 47 months (range, 15–75 months). There were no cases of a missed diagnosis at initial presentation. The mean time to union was 4.5 months for the neck fracture and 8.2 months for the shaft. There were no cases of avascular necrosis of the femoral head or non-union of the neck fracture. The mean Harris Hip Score was (85 ± 4.3). Complications included two cases of shaft fracture non-union and one case of peroneal nerve palsy. Heterotopic ossification at the tip of the greater trochanter was evident in two cases without causing any functional deficit. The current study suggests that reconstruction nailing produces satisfactory clinical and functional results in the mid-term. The complications involved only the femoral shaft fracture and were successfully treated with a single operative procedure.
doi:10.1007/s11751-011-0117-0
PMCID: PMC3150652  PMID: 21779894
Femoral shaft fractures; Ipsilateral hip; Reconstruction nail
9.  Scaphoid reconstruction with vascularized bone grafts from the distal radius 
The aim of the present technical report is to describe the alternative solutions for the reconstruction of scaphoid nonunions with pedicled vascularized bone grafts from the distal radius. The surgical technique for the reconstruction A. of proximal scaphoid nonunions with pedicled bone grafts (based on the 1,2 or on the 2,3 intercomparmtental arteries) or with capsular bone grafts from the dorsal distal radius and B. of waist nonunions of the scaphoid with grafts from the palmar distal radius, pedicled on the palmar carpal arch, is presented. Vascularized bone grafts from the adjacent radius are used for the treatment of scaphoid nonunions to enhance union and to revascularize a nonviable proximal pole. The most suitable graft is selected according to the location of the nonunion (at the waist or the proximal pole of the scaphoid) and to the previous procedures/scars at the wrist level.
doi:10.1007/s12593-009-0003-x
PMCID: PMC3453212  PMID: 23129932
Scaphoid nonunions; Vascularized bone grafts; Pedicled; Distal radius
10.  Influence of Interleukin 1α (IL-1α), IL-4, and IL-6 Polymorphisms on Genetic Susceptibility to Chronic Osteomyelitis▿  
Clinical and Vaccine Immunology : CVI  2008;15(12):1888-1890.
The association between cytokine gene polymorphisms and chronic osteomyelitis was investigated in order to determine whether genetic variability in cytokine genes predisposes to osteomyelitis susceptibility. Significant genotypic and allelic associations were observed between interleukin 1α (IL-1α) −889-C/T, IL-4 −1098-G/T and −590-C/T, and IL-6 −174-G/C polymorphisms and osteomyelitis in the Greek population, pointing towards their potential involvement in osteomyelitis pathogenesis.
doi:10.1128/CVI.00209-08
PMCID: PMC2593176  PMID: 18971305
11.  Epidural bleeding after ACL reconstruction under regional anaesthesia: a case report 
Cases Journal  2009;2:6732.
Introduction
Epidural bleeding as a complication of catheterization or epidural catheter removal is often associated with perioperative thromboprophylaxis especially in adult reconstructive surgery.
Case presentation
We report on a case of a 19 years old male athlete that underwent anterior cruciate ligament reconstruction, receiving low molecular weight heparin for thromboprophylaxis and developed an epidural hematoma and subsequent cauda equina syndrome two days after removal of the epidural catheter. An urgent magnetic resonance imaging scan revealed an epidural hematoma from the level of L3 to L4. Emergent decompression and hematoma evacuation resulted in patient's significant neurological improvement immediately postoperatively.
Conclusion
A high index of clinical suspicion and surgical intervention are necessary to prevent such potentially disabling complications especially after procedures on a day-case basis and early patient's discharge.
doi:10.1186/1757-1626-2-6732
PMCID: PMC2740288  PMID: 19829853
12.  Outcome after tantalum rod implantation for treatment of femoral head osteonecrosis 
Acta Orthopaedica  2009;80(1):20-25.
Background and purpose Tantalum rod implantation has recently been proposed for treatment of early stages of femoral head osteonecrosis. The purpose of our study was to report the early results of its use in pre- and post-collapse stages of the disease.
Methods We studied prospectively 27 patients who underwent tantalum rod implantation for treatment of nontraumatic femoral head osteonecrosis between December 2000 and September 2005. Patients were evaluated radiologically and clinically using the Steinberg classification and the Harris hip score (HHS). Disease stage varied between stages II and IV. Mean follow-up time was 38 (15–71) months.
Results 1 patient (1 hip) died 15 months after surgery for reasons unrelated to it. 13 of 26 hips remained at the same radiographic stage, and 13 deteriorated. Mean HHS improved from 49 to 85. 6 patients required conversion to total hip arthroplasty. When the procedure was used for stages III and IV, both radiological outcome and revision rates were worse than for the stage II hips. There was, however, no difference in postoperative HHS between patients at pre- and post-collapse stages at the time of initial evaluation. Survivorship, with revision to THA as the endpoint, was 70% at 6 years.
Interpretation The disease process does not appear to be interrupted, but there was a significant improvement in hip function initially in most hips. Tantalum rod implantation is a safe “buy-time” technique, especially when other joint salvage procedures are not an option. Appropriate patient selection and careful rod insertion are needed for favorable results.
doi:10.1080/17453670902804877
PMCID: PMC2823224  PMID: 19297785
13.  Survivorship of Monoblock Trabecular Metal Cups in Primary THA 
Monoblock trabecular metal cups are made of a novel porous material intended to enhance ingrowth and improve fixation. We prospectively followed 223 consecutive patients with 245 trabecular metal acetabular cups implanted during primary total hip arthroplasties to determine the overall survivorship of the implant, and any association of survivorship to primary diagnosis and age, and to determine the fate of polar gaps and cysts. Minimum followup was 36 months (mean, 60 months; range, 36–112 months). Patients were assessed with the Harris Hip score and the Oxford questionnaire and radiographically with standardized serial radiographs. At last followup, all cups were radiographically stable with no evidence of migration or progressive radiolucencies. The survivorship with reoperation as the end point was estimated at 98.75% with a 95% confidence interval. Three reoperations occurred during the first 36 months. The Harris hip score increased from 48 to 94 and the Oxford score was 16.4 at the last examination. We observed no difference in terms of survivorship among patients with osteoarthritis, osteonecrosis, or hip dysplasia. Seven of 14 (50%) osteoarthritis cysts and 10 of 33 (33.3%) polar gaps detected on postoperative radiographs decreased or filled, whereas none of the remainder deteriorated with time. Our midterm results suggest this implant may enhance fixation, but long-term followup is needed to confirm our findings.
Level of Evidence: Level IV Therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-007-0008-3
PMCID: PMC2505300  PMID: 18196389
14.  Relapsed clubfoot correction with soft-tissue release and selective application of Ilizarov technique 
The Ilizarov technique is an alternative for the treatment of complex foot deformities in children. The authors retrospectively reviewed children with relapsed clubfoot deformity, treated with soft tissue procedures and additional correction with an Ilizarov frame. Twelve consecutive patients (13 feet) with relapsed clubfoot deformity after previous surgical correction were reviewed. Treatment included open releases. An Ilizarov frame was applied as an adjunct in seven patients (mean age of 7.8 years) with severe deformity where complete intraoperative correction was not achieved. Clinical and radiographic assessment was undertaken. The mean Laaveg–Ponseti score, for the 7 feet treated with the Ilizarov frame, was 85.1 after minimum 4 years follow-up. One recurrence of forefoot deformity required metatarsal osteotomies. Postoperative radiographic measurements revealed values that can be considered as normal. Complications included pin tract infections (12% of inserted wires). Flat-topped talus was observed in 3 feet. Deformity correction was possible when soft tissue procedures were combined with the use of Ilizarov technique, in order to support and gradually improve surgical correction.
doi:10.1007/s11751-008-0049-5
PMCID: PMC2599798  PMID: 19057984
Clubfoot; Ilizarov; Recurrent; Relapsed; Release
15.  Integrative MicroRNA and Proteomic Approaches Identify Novel Osteoarthritis Genes and Their Collaborative Metabolic and Inflammatory Networks 
PLoS ONE  2008;3(11):e3740.
Background
Osteoarthritis is a multifactorial disease characterized by destruction of the articular cartilage due to genetic, mechanical and environmental components affecting more than 100 million individuals all over the world. Despite the high prevalence of the disease, the absence of large-scale molecular studies limits our ability to understand the molecular pathobiology of osteoathritis and identify targets for drug development.
Methodology/Principal Findings
In this study we integrated genetic, bioinformatic and proteomic approaches in order to identify new genes and their collaborative networks involved in osteoarthritis pathogenesis. MicroRNA profiling of patient-derived osteoarthritic cartilage in comparison to normal cartilage, revealed a 16 microRNA osteoarthritis gene signature. Using reverse-phase protein arrays in the same tissues we detected 76 differentially expressed proteins between osteoarthritic and normal chondrocytes. Proteins such as SOX11, FGF23, KLF6, WWOX and GDF15 not implicated previously in the genesis of osteoarthritis were identified. Integration of microRNA and proteomic data with microRNA gene-target prediction algorithms, generated a potential “interactome” network consisting of 11 microRNAs and 58 proteins linked by 414 potential functional associations. Comparison of the molecular and clinical data, revealed specific microRNAs (miR-22, miR-103) and proteins (PPARA, BMP7, IL1B) to be highly correlated with Body Mass Index (BMI). Experimental validation revealed that miR-22 regulated PPARA and BMP7 expression and its inhibition blocked inflammatory and catabolic changes in osteoarthritic chondrocytes.
Conclusions/Significance
Our findings indicate that obesity and inflammation are related to osteoarthritis, a metabolic disease affected by microRNA deregulation. Gene network approaches provide new insights for elucidating the complexity of diseases such as osteoarthritis. The integration of microRNA, proteomic and clinical data provides a detailed picture of how a network state is correlated with disease and furthermore leads to the development of new treatments. This strategy will help to improve the understanding of the pathogenesis of multifactorial diseases such as osteoarthritis and provide possible novel therapeutic targets.
doi:10.1371/journal.pone.0003740
PMCID: PMC2582945  PMID: 19011694
16.  Migfilin’s elimination from osteoarthritic chondrocytes further promotes the osteoarthritic phenotype via β-catenin upregulation 
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.
doi:10.1016/j.bbrc.2012.12.008
PMCID: PMC3764434  PMID: 23237804
osteoarthritis; Migfilin; β-catenin; chondrocytes; extracellular matrix
17.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
Objective
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Methods
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
Results
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite 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 radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Conclusion
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.
doi:10.1016/j.joca.2010.10.027
PMCID: PMC3236091  PMID: 21059398
18.  New Sequence Variants in HLA Class II/III Region Associated with Susceptibility to Knee Osteoarthritis Identified by Genome-Wide Association Study 
PLoS ONE  2010;5(3):e9723.
Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of ∼4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43×10−8 for rs7775228 and 6.73×10−8 for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA.
doi:10.1371/journal.pone.0009723
PMCID: PMC2841168  PMID: 20305777

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