Espondilodiscitis lumbar, presentación infrecuente de gota tofácea

Microcrystalline arthropathy is a very common pathology in the general population, being the axial presentation a rare condition. We present the case of an older man with disabling low back pain which required a biopsy to reach a diagnosis of spinal gout despite a previous lumbar magnetic resonance imaging. After introducing the classic treatment there was a significant clinical improvement. Diagnosis is complicated, so it is essential to include clinical suspicion of chronic low back pain.La artropatía por microcristales es una patología muy frecuente en la población general, siendo la presentación axial una condición rara. Presentamos el caso de un varón de edad avanzada con dolor lumbar incapacitante que precisó la realización de biopsia para llegar al diagnóstico de gota espinal pese a la realización previa de una resonancia magnética lumbar. Tras la instauración del tratamiento clásico se produjo una gran mejoría clínica. El diagnóstico es complicado por lo que es imprescindible incluir la sospecha clínica ante un dolor lumbar crónico

The poor accuracy of D-dimer for the diagnosis of prosthetic joint infection but its potential usefulness in early postoperative infections following revision arthroplasty for aseptic loosening

Background: D-dimer was introduced in 2018 as an alternative biomarker for C-reactive protein (CRP) in the diagnostic of prosthetic joint infection (PJI) criteria of the Musculoskeletal Infection Society. We assessed the accuracy of plasma D-dimer for the diagnosis of early, delayed, and late PJI according to Infectious Diseases Society of America (IDSA) criteria, and whether persistently high levels of D-dimer in cases of aseptic loosening (AL) may be predictive of subsequent implant-related infection. Methods: A prospective study of a consecutive series of 187 revision arthroplasties was performed at a single institution.Septic (n = 39) and aseptic revisions (n = 141) were classified based on IDSA criteria. Preoperative assessment of CRP, erythrocyte sedimentation rate (ESR) and D-dimer was performed. Receiver operating curves were used to determine maximum sensitivity and specificity of the biomarkers. The natural progress of D-dimer for AL cases was followed up either until the date of implant-related infection at any time during the first year or 1 year after revision in patients without failure. Clinical outcomes for those AL cases included infection-related failure that required a new surgery or need for antibiotic suppression. Results: Preoperative D-dimer level was significantly higher in PJI cases than in AL cases (p = 0.000). The optimal threshold of D-dimer for the diagnosis of PJI was 1167 ng/mL. For overall diagnosis of PJI, C-reactive protein (CRP) achieved the highest sensitivity (84.6%), followed by erythrocyte sedimentation rate (ESR) and D-dimer (82% and 71.8%, respectively). Plasma D-dimer sensitivity was lower for all PJI types. When combinations of 2 tests were studied, the combined use of ESR and CRP achieved the best accuracy for all types of PJI (76.9%). 4.25% of AL cases had implant failure due to implant-related infection during the first year after the index revision arthroplasty, only the cases with early failure maintained high D-dimer levels

Genetic polymorphisms of the wint receptor LRP5 are differentially associated with trochanteric and cervical hip fractures

Producción CientíficaPurpose. Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We planned to test the hypothesis that genetic factors have different influences on both types of fractures. Methods. Ten polymorphisms of genes known to play an important role in skeletal homeostasis (estrogen receptor alpha [ESR1], aromatase [CYP19A1], type I collagen [COL1A1], and lipoprotein receptor-related protein 5 [LRP5]) were analyzed in 471 Spanish patients with fragility hip fractures. Results. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (p-value 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci, in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with 1 or 2 rare alleles, and 7.5 in those with 3 or 4 rare alleles (p-value for trend 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1 and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or in an extended group of 818 patients. Conclusions. These results suggest LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies

Non-synonymous WNT16 polymorphisms alleles are associated with different osteoarthritis phenotypes

Hereditary factors have a strong influence on osteoarthritis (OA). The Wnt pathway is involved in bone and cartilage homeostasis. Hence, we hypothesized that allelic variations of WNT16 could influence the OA phenotype. We studied 509 Caucasian patients undergoing joint replacement due to severe primary OA. Radiographs were used to classify the OA as atrophic or hypertrophic. Two nonsynonymous polymorphisms of WNT16 (rs2707466 and rs2908004) were analyzed. The association between the genotypes and the OA phenotype was analyzed by logistic regression and adjusted for age and body mass index. A genotype-phenotype association was found in the sex-stratified analysis. Thus, there was a significant difference in the genotypic frequencies of rs2707466 between hypertrophic and atrophic hip OA in males (p = 0.003), with overrepresentation of G alleles in the hypertrophic phenotype (OR 2.08; CI 1.28-3.38). An association in the same direction was observed between these alleles and the type of knee OA, with G alleles being more common in the hypertrophic than in atrophic knee phenotypes (p = 0.008; OR 1.956, CI 1.19-3.19). Similar associations were found for the rs2908004 SNP, but it only reached statistical significance for knee OA (p = 0.017; OR 0.92, CI 0.86-0.989). This is the first study attempting to explore the association of genetic variants with the OA phenotype. These data suggest the need to consider the OA phenotype in future genetic association studies of OA

Analysis of serum proteome after treatment of osteoporosis with anabolic or antiresorptive drugs

The aim of the study was to explore new markers in serum proteome associated with the response to antiosteoporosis drugs, namely teriparatide and denosumab. We obtained serum samples from 14 patients with osteoporosis, both at baseline and after 6 months of treatment with teriparatide (n = 10) or denosumab (n = 4). Samples were analyzed by nanoliquid chromatography coupled to high-resolution mass spectrometry on a QTOF 5600 (SCIEX) apparatus. The spectrometry data were analyzed with Mascot against the UniProtKB base and then several quality-control filters were applied for the identification of peptides (false discovery rate, FDR q < 0.02) and their quantification (FDR q < 0.05). In the group treated with teriparatide, 28 proteins were identified with significant differences before and after treatment. A pathway analysis by using the Reactome database revealed significant enrichment in the Insulin Like Growth Factor 1 (IGF-I) (FDR q 4 × 10-²) and innate immune system (FDR q 2 × 10-³) pathways. Among patients treated with denosumab, we observed significant differences in the levels of 10 proteins, which were also enriched in the pathways related to the innate immune system (FDR q 3 × 10-²). These results suggest that the innate immune system may be involved in the response to antiosteoporosis drugs.Funding: Supported by grants from FEIOMM (Grant No.17/0025) and ProteoRed-ISCIII. Acknowledgments: Alvaro del Real received support by the postdoctoral grant Augusto Gonzalez de Linares of the University of Cantabria

Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

Sclerostin, encoded by the SOST gene, works as an inhibitor of the Wnt pathway and therefore is an important regulator of bone homeostasis. Due to its potent action as an inhibitor of bone formation, blocking sclerostin activity is the purpose of recently developed antiosteoporotic treatments. Two bone-specific transcription factors, RUNX2 and OSX, have been shown to interact and co-ordinately regulate the expression of bone-specific genes. Although it has been recently shown that sclerostin is targeted by OSX in mice, there is currently no information of whether this is also the case in human cells. We have identified SP-protein family and AML1 consensus binding sequences at the human SOST promoter and have shown that OSX, together with RUNX2, binds to a specific region close to the transcription start site. Furthermore, we show that OSX and RUNX2 activate SOST expression in a co-ordinated manner in vitro and that SOST expression levels show a significant positive correlation with OSX/ RUNX2 expression levels in human bone. We also confirmed previous results showing an association of several SOST/RUNX2 polymorphisms with bone mineral density

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

Producción CientíficaWe reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in 26 osteoarthritis. We aimed to confirm those results by analyzing β-catenin levels and explored potential genetic 27 and epigenetic mechanisms involved. 28 β-Catenin gene expression and nuclear levelswere analyzed by real time PCR and confocal immunofluorescence. 29 Increased nuclear β-catenin was found in osteoblasts isolated from patients with osteoarthritis (99 ± 4 30 units vs. 76 ± 12, p = 0.01, n = 10), without differences in gene transcription, which is consistent with 31 a post-translational down-regulation of β-catenin and decreased Wnt pathway activity. 32 Twenty four single nucleotide polymorphisms (SNPs) of genes showing differential expression between fractures 33 and osteoarthritis (WNT4, WNT10A, WNT16 and SFRP1) were analyzed in DNA isolated from blood of 853 pa- 34 tients. The genotypic frequencies were similar in both groups of patients, with no significant differences. 35 Methylation ofWnt pathway genes was analyzed in bone tissue samples (15 with fractures and 15 with osteo- 36 arthritis) by interrogating a CpG-based methylation array. Six genes showed significant methylation differences 37 between both groups of patients: FZD10, TBL1X, CSNK1E, WNT8A, CSNK1A1L and SFRP4. The DNA demethylating 38 agent 5-deoxycytidine up-regulated 8 genes, including FZD10, in an osteoblast-like cell line, whereas it down- 39 regulated other 16 genes. 40 In conclusion,Wnt activity is reduced in patientswith hip fractures, in comparisonwith thosewith osteoarthritis. 41 It does not appear to be related to differences in the allele frequencies of the Wnt genes studied. On the other 42 hand, methylation differences between both groups could contribute to explain the differences inWnt activit

Método sensible para monitorizar la migración de las células madre mesenquimales de la médula ósea en modelos murinos

Resumen: Objetivo: Las células madre mesenquimales (MSCs) son atractivas en la terapia regenerativa de patologías humanas. En los modelos murinos, en los que se trasplantan MSCs humanas, es muy importante poder distinguir el origen de las MSCs identificadas en los órganos de ratones. El objetivo de este estudio fue determinar el rendimiento del análisis basado en PCR de secuencias Alu humanas para detectar ADN humano después de la infusión de células madre de médula ósea humana (hBMSCs) en ratones inmunodeficientes. Material y método: Las hBMSCs se obtuvieron de la cabeza femoral de pacientes sometidos a cirugía de reemplazo de cadera. Se infundieron 106 hBMSCs por vía intravenosa mediante inyección en el seno retro‐orbitario de ratones NOD/SCID. Después se evaluó la presencia de ADN humano en pulmón, hígado y hueso. Resultados: En mezclas de ADN in vitro, el ADN humano se detectó fácilmente con una buena relación logarítmica‐lineal. De manera similar, cuando se mezclaron osteoblastos humanos y de ratón, se detectaron fácilmente 1‐10 células humanas entre 105 células de ratón. Asimismo, se detectó el ADN humano en los pulmones 1 y 7 días después de las infusiones celulares en ratones NOD/SCID. Sin embargo, el ADN humano se detectó de manera inconsistente en el hígado y los huesos. Conclusión: La detección de secuencias Alu es un procedimiento eficaz para detectar ADN humano. Los resultados confirman que la mayoría de las hBMSCs inyectadas por vía intravenosa quedan atrapadas en los pulmones. Por lo tanto, de cara al tratamiento de trastornos esqueléticos, se necesitan procedimientos para aumentar la migración de dichas células al hueso

Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication

Objectives. Genes explaining the susceptibility to osteoporosis have not been fully elucidated. Our objective was to explore the association of polymorphisms capturing common variations of the lipoprotein receptor related protein (LRP) 5 and 6 genes, encoding two Wnt receptors, with femoral neck bone mineral density (BMD) and osteoporotic fractures of the spine and the hip. Design. Cross-sectional, case-control and replication genetic association study. Methods. Thirty nine tagging and functional single nucleotide polymorphisms (SNP) were analyzed in a group of 1043 postmenopausal women and 394 women with hip fractures. The results were replicated in a different group of 342 women. Results. Three SNPs of the LRP6 gene were associated with BMD (nominal uncorrected pvalues< 0.05) in the discovery cohort. One showed a significant association after multiple test correction; two of them were also associated in the replication cohort, with a combined standardized mean difference of 0.51 (p=0.009) and 0.65 (p<0.0001) across rs11054704 and rs2302685 genotypes. In the discovery cohort, several LRP5 SNPs were associated with vertebral fractures (odds ratio 0.67; p=0.01), with hip fractures (unadjusted odds ratios between 0.59 and 1.21, p=0.005-0.033, but not significant after multiple test- or age-adjustment), and with height and the projected femoral neck area, but not with BMD. Transcripts of LRP5 and LRP6 were similarly abundant in bone samples. Conclusions. In this study we found common polymorphisms of LRP5 associated with osteoporotic fractures, and polymorphisms of the LRP6 gene associated with BMD, thus suggesting them as likely candidates to contribute explaining the hereditary influence on osteoporosis

Influencia del oxígeno a alta concentración en cámara hiperbárica sobre el metabolismo óseo

RESUMEN: Objetivos: Conocer las acciones del oxígeno a alta concentración en cámara hiperbárica (CH) sobre la expresión de genes relacionados con el metabolismo óseo en líneas celulares osteoblasticas y hueso trabecular humano. Material y métodos: Se analizó la expresión diferencial de varios genes relacionados con el metabolismo óseo (SOST, RUNX2, MMP14, OPG, HIF‐1α y SIRT1) en dos líneas celulares osteoblasticas humanas (Saos y Super‐Saos) y en fragmentos de hueso trabecular humano sometidos a una, tres o cinco sesiones de CH (90 minutos, oxigeno 100%; 2,3 atmosferas). En cada experimento se utilizó un control que no recibió CH. Resultados: No encontramos diferencias significativas tras la CH en la expresión de los genes estudiados, ni en las células ni en hueso trabecular. Solo en la línea celular Super‐Saos la expresión de OPG tras 5 sesiones de CH descendió 6 veces con respecto a la del grupo control (2‐ΔCt de 72; p=0,01). Conclusiones: El oxígeno a alta concentración en cámara hiperbárica no parece tener influencia en la expresión de genes relacionados con el metabolismo óseo