Key molecule explains why bones weaken with age

Osteoporosis affects around 200 million women worldwide.

One in 3 women and 1 in 5 men aged 50 and above are thought to experience a bone fracture in their lifetime as a result of osteoporosis.

In the United States, estimates indicate that 44 million people over 50 live with the condition, making it a major public health issue.

New research brings us closer to understanding the process that leads to bone degradation in osteoporosis and to potential new ways in which the condition could be tackled.

The findings explain a key molecular dynamic that accounts for the progressive frailty of our bones as we age.

Dr. Sadanand Fulzele, a bone biologist who works in the Department of Orthopaedic Surgery at Augusta University in Georgia, is a co-corresponding researcher and the last author of the new paper, which was published in the Journal of Gerontology: Biological Sciences.

Zooming in on a small molecular culprit

Dr. Fulzele and colleagues explain the process of bone formation — which starts with mesenchymal stem cells. These are stem cells that can be found in our bone marrow and that can go on to form as cartilage, bone, or the fat in bone marrow.

One of the factors that influence which form these cells will eventually take is a signaling molecule called stromal-cell-derived factor (SDF-1).

Previous research by the same team had shown how important SDF-1 is for the differentiation of mesenchymal stem cells into the different cells crucial to bone health.

Both in vitro and in vivo studies conducted by the researchers showed the key role of this signaling molecule for bone formation. SDF-1 is also important for bone repair and protects bone cells from oxidative stress, which is the imbalance between free radicals and antioxidants in the body that eventually leads to DNA damage and disease.

Also, previous studies had demonstrated that SDF-1 levels decline in aging mice; so, in this study, Dr. Fulzele and team wanted to understand precisely how this molecule’s levels are regulated.

In some of his former research, Dr. Fulzele had shown that a small molecule called microRNA-141-3p stops vitamin C, a key antioxidant, from reaching our bone cells.

The team already knew that the molecule can stop mesenchymal stem cells from differentiating into other cells, as well as the fact that microRNA-141-3p increases with age. So, Dr. Fulzele and team hypothesized that microRNA-141-3p lowers SDF-1, and that this is one of the main ways in which this small molecule stops healthy bone formation.

Restoring normal bone function despite age

To test this, Dr. Fulzele and colleagues analyzed mesenchymal cells from both humans and mice. In young cells, they found that levels of microRNA-141-3p were low. However, in old cells, the levels of this molecule had tripled. The opposite was true for SDF-1 levels.

Then, the researchers injected microRNA-141-3p into mesenchymal stem cells obtained from adults aged 18–40, as well as from seniors aged 60–85 who had undergone orthopedic surgery.

Injecting microRNA-141-3p made SDF-1 levels plummet and caused the stem cells to make more fat instead of bone cells. With age, explain the researchers, making fat cells rather than bone cells becomes easier.

Also, the team added microRNA-141-3p to bone cells, which worsened bone function. However, applying a microRNA-141-3p inhibitor improved bone function.

The findings, explains Dr. Fulzele, suggest that one day, using a microRNA-141-3p inhibitor could help stem cells continue differentiating into bone cells despite age and conditions such as osteoporosis.

The inhibitor, states Dr. Fulzele, “normalizes bone function. We think [a] clinical-grade inhibitor may help us do the same in people.”

“If you are 20 years old and making great bone,” he adds, “you would still have microRNA-141-3p in your mesenchymal stem cells. But when you are 81 and making weaker bone, you have a lot more of it.”

“You want it sort of in that sweet spot,” explains co-corresponding study author Dr. William D. Hill, a stem cell researcher from Augusta University. The researchers say that they are planning to move their findings into preclinical models, where they want to find ways of restoring healthy levels of microRNA-141-3p and SDF-1.

What we are trying to do is dial it back down from where [microRNA-141-3p is] being overexpressed due to factors like aging and oxidative stress and suppression of estrogen, and bring it back into a range that would effectively allow more normal bone formation.”

Dr. William D. Hill

“We have identified a number of microRNAs that change in the bone marrow stem cells with aging and we are going after each one of these to understand how they are working,” Dr. Hill adds.

“We are starting to take more of a biological systems approach, [whereby we are] not just changing one target molecule, but looking at how this network of molecules is changed with age or disease and how we can reach in and […] reset these different pathways.”

Source: Read Full Article