Ismael Calero-Paniagua

Polymorphisms in Autophagy Genes Are Associated with Paget Disease of Bone

Paget disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The main alteration resides in osteoclasts that increase in size, number and activity. Many osteoclasts have cytoplasmic inclusions that have been associated with protein aggregates, increasing the evidences of a possible deregulation of autophagy in the development of the PDB. Autophagy starts with encapsulation of the target into a double-membrane-bound structure called an “autophagosome.” It has been reported that at least 18 ATG genes (autophagy-related genes) are involved in autophagosome formation. We have studied the distribution of genotypes of the ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183 and ATG5 rs2245214 polymorphisms in a Spanish cohort of subjects with PDB and compared with healthy subjects. Our results show that being a carrier of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing PDB, whereas being a carrier of the T allele of ATG10 rs1864183 polymorphism decreased the risk of suffering the disease in our series. This is the first report that shows an association between autophagy and Paget Disease of Bone and requires further confirmation in other series.

Manifestaciones trombóticas en el síndrome SAPHO. Revisión de la literatura

SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome is a cluster of osteo-cutaneous manifestations that can lead to serious complications such as thrombosis of the subclavian vein or superior vena cava, mainly in patients with significant inflammatory involvement of the anterior-chest-wall. The objective of this study was to review the cases published in the medical literature related with the presence of thrombotic complications in patients diagnosed with SAPHO syndrome and to try to determine their possible pathogenic mechanism and risk factors. We analyzed 11 published reports of isolated clinical cases or case series, a total of 144 patients, which described a total of 15 cases of venous thrombosis. The clinical characteristics of these patients, evaluated to determine whether they meet the ASAS criteria for axial and peripheral spondyloarthritis, is analyzed the need for early diagnosis and treatment is highlighted.

Clinical and Genetic Advances in Paget’s Disease of Bone: a Review

Paget’s disease of bone (PDB) is the second most common metabolic bone disorder, after osteoporosis. It is characterised by focal areas of increased and disorganised bone turnover, coupled with increased bone formation. This disease usually appears in the late stages of life, being slightly more frequent in men than in women. It has been reported worldwide, but primarily affects individuals of British descent. Majority of PDB patients are asymptomatic, but clinical manifestations include pain, bone deformity and complications, like pathological fractures and deafness. The causes of the disease are poorly understood and it is considered as a complex trait, combining genetic predisposition with environmental factors. Linkage analysis identified SQSTM1, at chromosome 5q35, as directly related to the disease. A number of mutations in this gene have been reported, pP392L being the most common variant among different populations. Most of these variants affect the ubiquitin-associated (UBA) domain of the protein, which is involved in autophagy processes. Genome-wide association studies enlarged the number of loci associated with PDB, and further fine-mapping studies, combined with functional analysis, identified OPTN and RIN3 as causal genes for Paget’s disease. A combination of risk alleles identified by genome-wide association studies led to the development of a score to predict disease severity, which could improve the management of the disease. Further studies need to be conducted to elucidate other important aspects of the trait, such as its focal nature and the epidemiological changes found in some populations. In this review, we summarize the clinical characteristics of the disease and the latest genetic advances to identify susceptibility genes. We also list current available treatments and prospective options.

VAV3 Gene Polymorphism Is Associated with Paget's Disease of Bone

BACKGROUND AND AIMS Pagets disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The disease affects osteoclasts which increase in size, number, and activity. One of the etiopathogenic hypotheses is that the disease is genetic. It has been reported that Rho GEF Vav3 is an essential factor in the regulation of osteoclast function, and alteration of the VAV3 gene could influence the development of the disease. The aim of our study was to perform an association study between variants of the VAV3 gene and the risk of developing Pagets disease of bone. PATIENTS AND METHODS The genotypic and allelic distribution of the VAV3 c.892A>T/p.T298S (rs7528153) polymorphism was compared between a cohort of 238 Spanish subjects with PDB and a cohort of 253 healthy subjects. RESULTS Our results indicated that individuals carrying the VAV3 rs7528153 TT genotype were at a significantly increased risk of developing PDB (p < 0.001, odds ratio [OR] = 3.15, 95% confidence interval [95% CI] = 1.77-5.61). CONCLUSIONS These results suggest that inheriting the VAV3 rs7528153 polymorphism is a likely susceptibility factor for developing Pagets disease of bone.

Another Gouty Tophus? The Many Faces of the Enchondroma

Los tumores óseos primarios de las manos son raros (2-5%), siendo el más frecuente el encondroma1,2. Los encondromas suelen aparecer en la segunda década de la vida, pero pueden hacerlo a cualquier edad. El 50% se localiza en las falanges proximales, seguidas en frecuencia por los huesos metacarpianos y las falanges medias. Los pacientes suelen permanecer asintomáticos, aunque en ocasiones pueden presentar aumento de volumen y deformidad de los dedos, dolor o sufrir fracturas patológicas secundarias a la expansión y remodelado de la lesión. La presentación de múltiples encondromas se conoce como enfermedad de Ollier3,4. Varón de 82 años diagnosticado de gota, consulta por tumoración en la segunda falange del tercer dedo de la mano izquierda de meses de evolución (fig. 1A y B). Dada la rareza de un tofo gotoso en dicha localización, se realizó radiografía simple (fig. 1C y D), objetivándose una lesión lítica expansiva. Posteriormente, se solicitó resonancia magnética nuclear (RMN), cuyos hallazgos eran

Influence Of Angiogenic Mediators And Bone Remodelling In Paget´s Disease Of Bone

Paget´s disease of bone (PDB) is characterized by increased bone resorption followed by an excessive compensatory bone formation, with an abnormal bone structure with altered mechanical properties. Pagetic bone also has a higher vascularization and marrow fibrosis. Despite of pagetic bone being a highly vascularized tissue, there are no studies on the plasma levels of angiogenic mediators in the different states of the disease; moreover, the effect of PDB treatment on plasma levels of these angiogenic mediators is not very well known. The aim of this study was to analyse plasma levels of cytokines implicated in the increased bone turnover (OPG, RANKL, sclerostin) and hypervascularization (VEGF, PGF, ENG) observed in PDB and their evolution and response to zoledronic acid treatment in 70 PDB patients, 29 with an active disease measured by plasma alkaline phosphatase (ALP). Plasma ALP concentration was higher in active PDB than in inactive PDB patients, whereas there were no differences in OPG, RANKL, sclerostin, VEGF, PGF and ENG plasma levels between active and inactive PDB patients. ALP decreased at 3 and 12 months after zoledronic acid treatment. RANKL levels were reduced and sclerostin levels were increased after 12 months of treatment. PGF levels were lower 12 months after zoledronic acid treatment, whereas there were no differences in plasma VEGF and ENG after zoledronic acid treatment. Summarizing, zoledronic acid treatment is associated to decreases in plasma levels of ALP, RANKL, sclerostin and P1GF in active PDB patients. This treatment may reduce bone turnover and might reduce the pathological vascularisation typical of pagetic bone.

Polymorphisms in genes implicated in base excision repair (BER) pathway are associated with susceptibility to Paget's disease of bone

Pagets disease of bone (PDB) is a chronic bone metabolic disorder. Currently, PDB is the second most frequent bone disorder. PDB is a focal disorder affecting the skeleton segmentally but the cause of which is unknown. It has been hypothesised that somatic mutations could be responsible for the mosaicism described in PDB patients. Therefore, our hypothesis is that defective response to DNA damage may lead to somatic mutations favouring an increased risk of PDB. So that we have analysed polymorphisms in DNA repair genes involved in the BER, NER and DSBR pathways in order to evaluate the role of these variants in modulating PDB risk. We found statistically significant differences in genotypic and allelic distribution for polymorphisms in genes implicated in the BER pathway. Our results showed that carrying the allele T of XRCC1 rs1799782 polymorphism and the allele G of APEX rs1130409 polymorphism increased the risk of developing PDB. These polymorphisms could cause a lower DNA repair efficiency and this might lead to local somatic mutations favouring bone metabolic alterations characteristic of PDB. This is the first report showing an association between polymorphism in genes implicated in the BER pathway with PDB.

Role of Bone Morphogenetic Protein 2 Polymorphisms in Bone Mineral Density after the Start of Treatment with Atorvastatin

One of the pleiotropic effects of statins is their capacity to increase bone formation. This is due to, among other things, they modify BMP-2 pathway. Several experimental studies have confirmed that statins have bone anabolic properties but the consequences in bone metabolism in the clinical practice are very variable. Our hypothesis is that the clinical variability in bone metabolism response could be attributed, among other causes, to genetic factors. Therefore, we analysed polymorphisms in BMP-2 gene (rs235768, rs1980499, rs2273073 and rs1005464) in order to evaluate the role of these variants in modulating bone metabolism response to statins treatment in patients with acute coronary syndrome. Our results showed that being a carrier of the variant allele T of BMP2 rs2273073 polymorphism was associated with an increased in the total hip BMD following atorvastatin therapy. This is the first report showing an association between a polymorphism in BMP-2 gene and bone changes in response to atorvastatin treatment. This report reinforces the hypothesis that genetic factors are crucial in the clinical variability of bone metabolism changes in response to statin treatment. This article is protected by copyright. All rights reserved.

¿Otro tofo gotoso? Las múltiples caras del encondroma

Los tumores óseos primarios de las manos son raros (2-5%), iendo el más frecuente el encondroma1,2. Los encondromas sueen aparecer en la segunda década de la vida, pero pueden hacerlo cualquier edad. El 50% se localiza en las falanges proximaes, seguidas en frecuencia por los huesos metacarpianos y las alanges medias. Los pacientes suelen permanecer asintomátios, aunque en ocasiones pueden presentar aumento de volumen deformidad de los dedos, dolor o sufrir fracturas patológicas ecundarias a la expansión y remodelado de la lesión. La presenación de múltiples encondromas se conoce como enfermedad de llier3,4. Varón de 82 años diagnosticado de gota, consulta por tumoraión en la segunda falange del tercer dedo de la mano izquierda de

Metalosis como causa de dolor e inflamación en un paciente con prótesis de rodilla: descripción de un caso

A 72-year-old woman who had undergone unicompartmental arthroplasty in right knee 12 years earlier, presented with a 6-month history of pain in that knee, in the absence of fever or systemic symptoms. On physical examination, the knee was found to be swollen. Radiography revealed a prosthesis in the medial compartment, which remained unchanged since the partial knee replacement (Fig. 1). Arthrocentesis yielded a dark fluid (Fig. 2) with 150 white blood cells/ L (75% polymorphonuclear cells), glucose level at 90 mg/dL and proteins at 2 mg/dL. Culture of the joint fluid was negative. With the suspicion of metallosis, the patient was referred to the orthopedics department and underwent total knee replacement. The pathological study of a specimen of synovial tissue showed macrophages with a blackish pigment in the cytoplasm and lymphocytes (Figs. 3 and 4). At the present time, the patient is asymptomatic. Metallosis is defined as a corrosion due to the erosion of metallic components, which produces particles that induce a hypersensitivity reaction. It is generally asymptomatic and the development of pain or stiffness is due to the secondary loosening of the prosthesis.1 It may be suspected when lobulated osteolytic areas, with or without increased volume of the adjacent soft tissues, are detected on plain radiography. The differential diagnosis should include aseptic dislocation of the prosthesis and septic arthritis.2 Macroscopic examination shows a black pigmentation of the joint,