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MiR-146a controls age related bone loss

Victoria Saferding, Melanie Hofmann, Julia S. Brunner, Birgit Niederreiter, Melanie Timmen, Nathaniel Magilnick, Silvia Hayer, Gerwin Heller, Günter Steiner, Richard Stange, Mark Boldin, Gernot Schabbauer, Moritz Weigl, Matthias Hackl, Johannes Grillari, Josef S. Smolen, Stephan Blüml

Preprint posted on March 20, 2020 https://www.biorxiv.org/content/10.1101/2020.03.20.000174v1

mIR-146a: a molecular clock in bone aging?

Selected by Claire Simon & Sophie Morgani

I have a confession… until now, I have taken my skeleton for granted. I have naively regarded it as a static scaffold, perhaps because I have never broken a bone. In reality, bone is highly dynamic. It is continually remodeled and is one of the few organs that can regenerate itself, allowing breaks to mend. Throughout our lifetime, our bones are working hard to actively maintain themselves through a careful balancing act between bone formation, mediated by osteoblasts, and bone resorption, by osteoclasts. However, as we age, the balance tips in the favour of osteoclasts so that by around 40 years old, our bone mass is already in decline. As a consequence, our bones become more fragile and susceptible to fractures and breaks, and our ability to heal these injuries also declines. Lesson learned…I will appreciate my skeleton!

 

It is therefore critical to understand the mechanisms that underpin age-related bone degeneration. In this pre-print, Saferding et al. show that the change from net bone formation to resorption coincides with an increase in the expression of miR-146a. They find that deleting this factor halts the switch, resulting in prolonged bone formation and increased bone mass. In wild-type mice, peak bone mass is reached at around 4 months of age and subsequently declines but, in the absence of miR-146a, bone mass increases until 12 months and peak bone mass is sustained until 16 months. This effect correlates with an increase in the expression of pro-osteoblast WNT ligands, WNT signaling activity, and elevated bone-forming activity. Thus, the authors hypothesize that miR-146a is a molecular clock in bone aging.

Open Questions

 

This study opens several interesting questions:

 

  • What drives the increase in mIR-146a expression before bone mass decline?
  • Is the “anti-aging” effect of miR-146a mediated by the increase in WNT signaling alone and which cells secrete/respond to WNT?
  • The effect of miR-146 is more apparent in female than male mice. What is underpins the sex-specific differences in miR-146 action?
  • miR-146a has anti-inflammatory activity in various contexts and inflammation is closely linked to bone aging. Is the inflammation response altered in vivo in miR-146a mutants and does this contribute to its role?

 

Posted on: 12th May 2020

doi: https://doi.org/10.1242/prelights.20580

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