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.

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

Evaluation of different approaches used to study membrane permeabilization by actinoporins on model lipid vesicles

30-07-2020

Release of aqueous contents from model lipid vesicles has been a standard procedure to evaluate pore formation efficiency by actinoporins, such as sticholysin II (StnII), for the last few decades...

Read more

ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity

01-07-2020

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. A-to-I editing of RNA is a widespread posttranscriptional process that has recently emerged as an important mechanism...

Read more

Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in Drosophila

29-05-2020

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca2+ peak that triggers muscle contraction, but mechanistic details remain unknown...

Read more

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

30-04-2020

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the...

Read more

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

31-03-2020

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT 178R ↓S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3...

Read more

Identification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis

29-02-2020

Technical problems intrinsic to the purification of preribosome intermediates have limited our understanding of ribosome biosynthesis in humans. Addressing this issue is important given the implication of this biological process...

Read more

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

23-01-2020

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of...

Read more

Mip6 binds directly to the Mex67 UBA domainto maintain low levels of Msn2/4 stress-dependent mRNAs

23-12-2019

RNA-binding proteins (RBPs) participate in all steps of gene expression, underscoring their potential as regulators of RNA homeostasis. We structurally and functionally characterize Mip6, a four-RNA recognition motif (RRM)-containing RBP...

Read more

A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis

01-12-2019

Plasmalogens are glycerophospholipids with a hallmark sn-1 vinyl ether bond. These lipids are found in animals and some bacteria and have proposed membrane organization, signaling, and antioxidant roles. We discovered...

Read more

The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

01-11-2019

Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper...

Read more

Protector Members