Reference

Genome Biology 2015, 16:2. January 2015

Autores

Lorenzo de la Rica*, Antonio García-Gómez*, Natalia R Comet, Javier Rodríguez-Ubreva, Laura Ciudad, Roser Vento-Tormo, Carlos Company, Damiana Álvarez-Errico, Mireia García, Carmen Gómez-Vaquero and Esteban Ballestar

Resumen

Background

Monocyte-to-osteoclast conversion is a unique terminal differentiation process that is exacerbated in rheumatoid arthritis and bone metastasis. The mechanisms implicated in upregulating osteoclast-specific genes involve transcription factors, epigenetic regulators and microRNAs (miRNAs). It is less well known how downregulation of osteoclast-inappropriate genes is achieved.

Results

In this study, analysis of miRNA expression changes in osteoclast differentiation from human primary monocytes revealed the rapid upregulation of two miRNA clusters, miR-212/132 and miR-99b/let-7e/125a. We demonstrate that they negatively target monocyte-specific and immunomodulatory genes like TNFAIP3, IGF1R and IL15. Depletion of these miRNAs inhibits osteoclast differentiation and upregulates their targets. These miRNAs are also upregulated in other inflammatory monocytic differentiation processes. Most importantly, we demonstrate for the first time the direct involvement of Nuclear Factor kappa B (NF-?B) in the regulation of these miRNAs, as well as with their targets, whereby NF-?B p65 binds the promoters of these two miRNA clusters and NF-?B inhibition or depletion results in impaired upregulation of their expression.

Conclusions

Our results reveal the direct involvement of NF-?B in shutting down certain monocyte-specific genes, including some anti-inflammatory activities, through a miRNA-dependent mechanism for proper osteoclast differentiation.

Descripción

Los osteoclastos son células gigantes cuya función es degradar hueso, y se diferencian a partir de monocitos circulantes en sangre. En las articulaciones de pacientes con artritis reumatoide, este proceso de diferenciación está exacerbado. El aumento de osteoclastos en la articulación de los pacientes, provoca una excesiva resorción ósea, que da lugar a fracturas, y a la pérdida de función de la misma. Ademas, estas células son responsables de causar complicaciones óseas en mieloma multiple y en metastasis de algunos tumores (próstata y mama). En el presente estudio, hemos analizado los cambios en la expresión de 372 microRNAs durante el proceso de diferenciación de monocito a osteoclasto. Aparte de describir nuevos clusters de microRNAs importantes en la diferenciación, y validar sus genes diana, hemos descubierto el mecanismo por el cual su expresión es regulada. La familia de factores de transcripción NF-kB activa la expresión de estos miRNAs, y de esta manera contribuye al silenciamiento de genes específicos de monocito e inmunomoduladores, que no son necesarios para la función del osteoclasto. El tratamiento farmacológico con inhibidor de NF-kB impidió la expresión de los citados miRNAs, y retraso la diferenciación de los osteoclastos, lo cual abre una posible nueva vía de inhibición terapéutica que reduzca la severidad de las lesiones artríticas.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Cromatina y Enfermedad del Institut d'Investigació Biomèdica de Bellvitge está dirigido por el Dr Esteban Ballestar y centra su actividad investigadora en el estudio de mecanismos de desregulación epigenética en el sistema inmune, especialmente en el contexto de enfermedad autoinmune y en distintos modelos de diferenciación relevantes en enfermedades del sistema inmune. En los últimos años el laboratorio ha publicado diversos trabajos relacionados con la adquisición de alteraciones epigenéticas en distintos tipos celulares de enfermedades autoinmunes como el lupus eritematoso sistémico y la artritis reumatoide. Asimismo, el grupo ha realizado diversas contribuciones describiendo los mecanismos de adquisición de alteraciones. http://www.idibell.cat/modul/chromatin-and-disease/en Lorenzo de la Rica actualmente se encuentra en Londres (Reino Unido) trabajando como investigador postdoctoral en el Blizard institute, Queen Mary University of London, donde continua ampliando su formación en el campo de la Epigenetica, hidroximetilacion del ADN y enzimas TET con el Dr. Miguel Branco.

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