Longevity Briefs: How Mechanical Stress Keeps Your Bones Strong

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Osteoporosis – the loss of bone mass and strength with age – is a major cause of age-related disability. Fragile bones make fractures much more likely to occur from falls in older people. Osteoporosis is partly driven by the behaviour of stem cells within the bone marrow called BMMSCs (bone marrow mesenchymal stem cells). These cells are able to develop into either fat cells or bone-forming osteoblasts. In old age, these cells increasingly prefer to become fat cells, resulting in a reduction in bone formation and loss of bone tissue.

Fortunately, exercise can significantly slow the progression of osteoporosis, but there are still unanswered questions about exactly how. Cell culture studies suggest that BMMSCs respond directly to mechanical force, which promotes their development into osteoblasts. BMMSCs sense mechanical stress through force-sensitive protein channels in their membranes. These channels open in response to mechanical force, allowing positively charged ions like sodium and calcium to flow into the cell. They presumably play a role in BMMSC responses to exercise, but so far their importance hasn’t been proven in living organisms. In this study researchers set out to fill this knowledge gap, specifically for a protein channel called Piezo1.

The discovery:

Using genetic mouse models, cell culture experiments and biochemical tests, researchers were able to show that Piezo1 in BMMSCs acts as a brake on marrow fat formation by suppressing a local inflammatory signalling pathway.

Researchers first created a genetic mouse model in which certain cell types, including BMMSCs, lacked Piezo1. They found that these mice had lower bone mass and increased bone marrow fat cells compared with control mice, suggesting that Piezo1 was important for preserving bone mass. To be certain that this was due to the lack of Piezo1 in BMMSCs and not some other characteristic of the genetic mouse model, researchers took bone marrow from the genetically altered mice and transplanted it into unaltered mice. They found that this also resulted in loss of bone mass and gain of bone marrow fat compared to control mice who received bone marrow transplants from unmodified mice.

Researchers also tested the effects of Piezo1 when it came to exercise. Allowing mice to exercise by providing them with treadmills normally stimulates bone formation and reduces bone marrow fat, but researchers found that mice whose BMMSCs lacked Piezo1 did not benefit from 6 weeks of treadmill training.

In cell culture experiments, researchers were able to show that Piezo1 opening suppressed certain inflammatory pathways by activating a transcription factor (a regulator of gene activity) called Klf2. Conversely, lack of Piezo1 led to an increase in inflammatory signalling within BMMSCs, which promoted their development into fat cells. They also found that enhancing Klf2 activity or blocking several inflammatory signalling molecules prevented fat cell formation. Perhaps most importantly, when researchers used genetic techniques to either enhance Klf2 activity or suppress inflammatory signalling molecules in 8 week-old mice that lacked Piezo1, these mice recovered much of their lost bone mass.

The implications:

This study provides a concrete molecular link between mechanical force, inflammation, and the decision of marrow stem cells to become bone-forming cells or fat cells. Piezo1 converts physical signals (like those produced by exercise) into anti-inflammatory signals that favour bone formation. Researchers also provide some early animal evidence that this pathway can be manipulated, suggesting that it might be possible to partially reverse osteoporosis by targeting either Piezo1 or the inflammatory pathways it suppresses.

These findings will have to be confirmed in humans though – if you genetically delete an important protein and then administer a ‘fix’ for that deficiency, then of course you are likely to see beneficial results. When it comes to osteoporosis in humans, which develops over the course of many decades, the solution may not be so straightforward. In the meantime, there is good evidence that regular weight-bearing physical activity is a safe and highly effective way to support bone health with age.