Epigenetics of Osteoporosis: Critical Analysis of Epigenetic Epidemiology Studies

Osteoarthritis (OA) is an age-related disease with poorly understood pathogenesis. Recent studies have demonstrated that miRNA might play a key role in OA initiation and development. We reviewed recent publications and elucidated the connection between miRNA and OA cartilage anabolic and catabolic signals, including four signaling pathways: TGF-ß/Smads and BMPs signaling, associated with cartilage anabolism; and MAPK and NF-KB signaling, associated with cartilage catabolism. We also explored the relationships with MMP, ADAMTS and NOS (NitricOxide Synthases) families, as well as with the catabolic cytokines IL-1 and TNF-a. The potential role of miRNAs in biological processes such as cartilage degeneration, chondrocyte proliferation, and differentiation is discussed. Collective evidence indicates that miRNAs play a critical role in cartilage degeneration. These findings will aid in understanding the molecular network that governs articular cartilage homeostasis and in to elucidate the role of miRNA in the pathogenesis of O

Open Course Ware: una herramienta para la enseñanza de la medicina

La iniciativa internacional Open Course Ware (OCW) se ha desarrollado en los últimos años como un procedimiento para difundir de manera libre en la internet materiales docentes generados en diversas universidades, lo cual permite el aprovechamiento de éstos por parte de profesores y alumnos de otros lugares, convirtiendo así al OCW en una nueva herramienta aplicable al aprendizaje de la medicina

Epigenetic Mechanisms Regulating Mesenchymal Stem Cell Differentiation

Human Mesenchymal Stem Cells (hMSCs) have emerged in the last few years as one of the most promising therapeutic cell sources and, in particular, as an important tool for regenerative medicine of skeletal tissues. Although they present a more restricted potency than Embryonic Stem (ES) cells, the use of hMCS in regenerative medicine avoids many of the drawbacks characteristic of ES cells or induced pluripotent stem cells. The challenge in using these cells lies into developing precise protocols for directing cellular differentiation to generate a specific cell lineage. In order to achieve this goal, it is of the upmost importance to be able to control de process of fate decision and lineage commitment. This process requires the coordinate regulation of different molecular layers at transcriptional, posttranscriptional and translational levels. At the transcriptional level, switching on and off different sets of genes is achieved not only through transcriptional regulators, but also through their interplay with epigenetic modifiers. It is now well known that epigenetic changes take place in an orderly way through development and are critical in the determination of lineage-specific differentiation. More importantly, alteration of these epigenetic changes would, in many cases, lead to disease generation and even tumour formation. Therefore, it is crucial to elucidate how epigenetic factors, through their interplay with transcriptional regulators, control lineage commitment in hMSCs

Epigenetics of Skeletal Diseases

PURPOSE OF REVIEW: Epigenetic mechanisms modify gene activity in a stable manner without altering DNA sequence. They participate in the adaptation to the environment, as well as in the pathogenesis of common complex disorders. We provide an overview of the role of epigenetic mechanisms in bone biology and pathology. RECENT FINDINGS: Extensive evidence supports the involvement of epigenetic mechanisms (DNA methylation, post-translational modifications of histone tails, and non-coding RNAs) in the differentiation of bone cells and mechanotransduction. A variety of epigenetic abnormalities have been described in patients with osteoporosis, osteoarthritis, and skeletal cancers, but their actual pathogenetic roles are still unclear. A few drugs targeting epigenetic marks have been approved for neoplastic disorders, and many more are being actively investigated. Advances in the field of epigenetics underscore the complex interactions between genetic and environmental factors as determinants of osteoporosis and other common disorders. Likewise, they help to explain the mechanisms by which prenatal and post-natal external factors, from nutrition to psychological stress, impact our body and influence the risk of later disease.Acknowledgements: Supported by a grant from the Instituto de Salud Carlos III (PI 16/0915), which can be co-funded by the European Union (FEDER Funds)

Do epigenetic marks govern bone mass and homeostasis?

Bone is a specialized connective tissue with a calcified extracellular matrix in which cells are embedded. Besides providing the internal support of the body and protection for vital organs, bone also has several important metabolic functions, especially in mineral homeostasis. Far from being a passive tissue, it is continuously being resorbed and formed again throughout life, by a process known as bone remodeling. Bone development and remodeling are influenced by many factors, some of which may be modifiable in the early steps of life. Several studies have shown that environmental factors in uterus and in infancy may modify the skeletal growth pattern, influencing the risk of bone disease in later life. On the other hand, bone remodeling is a highly orchestrated multicellular process that requires the sequential and balanced events of osteoclast-mediated bone resorption and osteoblast-mediated bone formation. These processes are accompanied by specific gene expression patterns which are responsible for the differentiation of the mesenchymal and hematopoietic precursors of osteoblasts and osteoclasts, respectively, and the activity of differentiated bone cells. This review summarizes the current understanding of how epigenetic mechanisms influence these processes and their possible role in common skeletal diseases

Mecanismos de interacción osteoblasto-osteoclasto

El tejido óseo se renueva constantemente por la acción coordinada de osteoclastos y osteoblastos. Los osteocitos desempeñan un papel destacado en el inicio del remodelado en un lugar dado del esqueleto. Estos y otras células de estirpe osteoblástica producen diversos mediadores que modulan la diferenciación de los precursores osteoclásticos, paso inicial imprescindible para que comience la resorción. Entre ellos, son especialmente importantes el M-CSF y el RANKL

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

Expanding the etiology of oculo-auriculo-vertebral spectrum: a novel interstitial microdeletion at 1p36

The etiology of oculo-auriculo-vertebral spectrum (OAVS) is not well established. About half of patients show a positive family history. The etiology of familiar cases is unclear but appears genetically heterogeneous. This motivated us to report a case of OAVS with microtia, ptosis, facial microsomy, and fusion of vertebral bodies associated with a novel genetic etiology, including a deletion at 1p36.12-13. This case report expands on the genetic etiology of OAVS. Furthermore, it also expands the clinical manifestations of patients with interstitial deletions of the de 1p36.12-13 region

Hypercalcemia in patients with rheumatoid arthritis: a retrospective study

Objetivo: Investigar la prevalencia de hipercalcemia en pacientes con artritis reumatoide (AR) y analizar las características clínicas y las causas de la hipercalcemia. Material y métodos: Estudio retrospectivo de revisión basado en casos que incluyó 500 pacientes con AR. Se identificaron los pacientes con niveles de calcio aumentados en al menos dos ocasiones. Resultados: La hipercalcemia estuvo presente en 24 de los 500 pacientes con AR (4,8%). La edad osciló entre 50 y 80 años, con una media de 68±10 años. La duración media de la enfermedad fue de 10±7 años. De los pacientes con hipercalcemia, 22 eran mujeres postmenopáusicas (92%) y solo dos eran hombres (8%). El hiperparatiroidismo se encontró en 9 pacientes de la serie; solo un paciente tenía una hipercalcemia maligna debido a un mieloma múltiple, y un caso fue consecuencia de una intoxicación por vitamina D. En un paciente la hipercalcemia parecía relacionada con el síndrome calcio-alcalino. En el resto de pacientes, la hipercalcemia fue idiopática (8/24) o el estudio fue incompleto (4/24). No se encontró una relación evidente entre la actividad de la enfermedad y la aparición de hipercalcemia. Conclusión: Al igual que sucede en la población general, el hiperparatiroidismo primario es la causa más común de hipercalcemia en pacientes con AR. En algunos pacientes no se identificaron otros trastornos causantes de hipercalcemia, lo que plantea la posibilidad de una relación causal entre la AR y la hipercalcemia.Objetive: To investigate the prevalence of hypercalcemia in patients with rheumatoid arthritis (RA) and analyze the clinical features and causes of hypercalcemia. Material and methods: Retrospective case?based review study that included 500 patients with RA. Patients with increased calcium levels on at least two occasions were identified. Results: Hypercalcemia was present in 24 of the 500 RA patients (4.8%). The age ranged between 50 and 80 years, with a mean of 68±10 years. The mean duration of the disease was 10±7 years. Of the patients with hypercalcemia, 22 were postmenopausal women (92%) and only two were men (8%). Hyperparathyroidism was found in 9 patients in the series; only one patient had malignant hypercalcemia due to multiple myeloma, and one case was a consequence of vitamin D intoxication. In one patient, hypercalcemia appeared to be related to calcium?alkali syndrome. In the remaining patients, hypercalcemia was idiopathic (8/24) or the study was incomplete (4/24). No obvious relationship was found between disease activity and the appearance of hypercalcemia. Conclusion: As in the general population, primary hyperparathyroidism is the most common cause of hypercalcemia in patients with RA. In some patients, no other disorders causing hypercalcemia were identified, raising the possibility of a causal relationship between RA and hypercalcemia

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a caucasian family

We present a family with a rare mutation of the LRP6 gene and for the first time provide evidence for its association with low bone mineral density. Introduction: The Wnt pathway plays a critical role in bone homeostasis. Pathogenic variants of the Wnt co-receptor LRP6 have been associated with abnormal skeletal phenotypes or increased risk of cardiovascular events. Patient and methods: Here we report an index premenopausal patient and her family carrying a rare missense LRP6 pathogenic variant (rs141212743; 0.0002 frequency among Europeans). This variant has been previously associated with metabolic syndrome and atherosclerosis, in the presence of normal bone mineral density. However, the LRP6 variant was associated with low bone mineral density in this family, without evidence for association with serum lipid levels or cardiovascular events. Conclusion: Thus, this novel association shows that LRP6 pathogenic variants may be involved in some cases of early-onset osteoporosis, but the predominant effect, either skeletal or cardiovascular, may vary depending on the genetic background or other acquired factors.Funding: Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Natur