Genome Biology 2015, 16:2. January 2015


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



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.


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.


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.


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.



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. 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.

Descárgate este artículo aquí.
Más artículos en la revista SEBBM.


Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction


Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Read more

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour


To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Read more

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program


Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Read more

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements


/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Read more

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer


Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Read more

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton


Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Read more

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice


Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Read more

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons


Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Read more

Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions


Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts...

Read more

The Helicase PIF1 Facilitates Resection overSequences Prone to Forming G4 Structures


DNA breaks are complex lesions that can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR). The decision between these two routes of DNA repair is...

Read more

Protector Members