ApoE, a protein that is also implicated in Alzheimer’s and heart disease and is more prevalent in older people, interferes with bone healing, according to Duke University researchers.
They hope that this discovery will lead to new treatments to help people heal after injuries or surgeries, they share, in a study published in JCI Insight.
“When we decreased the protein level, aging was reversed,” senior author Gurpreet Baht, PhD, an assistant professor in the Duke Department of Orthopaedic Surgery, says in a media release from Duke University Medical Center.
“Not only was there more bone and healing happened faster, but it was also structurally more sound.”
Baht’s team confirmed that older people have more Apolipoprotein E, ApoE for short, than younger people.
The team found that 75-85 year olds had twice as much ApoE in their bloodstreams as 35-45 year olds, then found the same was true for 24-month-old mice versus 4-month-old mice, which approximate the same human age ranges.
Next, they wanted to figure out if and how ApoE affects the multi-step process of bone healing. When you break a bone, your body sends signals through the bloodstream to recruit cells to fix it. Some of those recruits, specifically skeletal stem cells, build up cartilage as a temporary scaffolding to hold the fracture together.
In the next step, more recruited cells mature into osteoblasts, bone-building cells, which lay strong, dense bone cells on top of the cartilage scaffolding. Finally, a different kind of cell eats up the cartilage scaffolds and osteoblasts fill those holes with bone, the release explains.
“Over time, this cartilage will continue to be resorbed and osteoblasts will continue to deposit new bone,” Baht continues. “After a few months of your arm or leg healing, there will be almost no cartilage anymore. And if you were to look at it five years out, there’d be no sign of an injury anymore.”
That’s if the bone-healing process works perfectly. But the researchers found that if they added ApoE to a petri dish with skeletal stem cells, fewer cells developed into osteoblasts and the osteoblasts were worse at building bones.
“We wanted to see if the cell population was more or less capable of becoming osteoblasts,” Baht adds. “[Normally,] you put these cells down in a petri dish for about a month and the dish becomes so hard that you can’t even scratch the surface because they’ve made two-dimensional bone there. ApoE-treated cells are still able to do this, they just don’t do it as much or as well.”
Next, the researchers created an intervention by injecting a virus which keeps mice from making ApoE protein. Circulating ApoE levels dropped by 75% and the healed bones contained one and a half-times more strong, hard bone tissue than bones of untreated mice.
Past researchers linked ApoE to Alzheimer’s disease and atherosclerosis, a disease in which fatty plaques narrow the arteries. Too little ApoE, and fat builds up and can cause cardiovascular issues. The liver virus which turned off ApoE production in mice acts permanently, so Baht’s next step is to investigate other interventions.
“You have to be careful,” Baht comments. “If a patient were to permanently decrease circulating ApoE levels, and then have a fatty meal, that fat might not get processed properly and could deposit in blood vessels. In our future studies, we’re going to try to temporarily lower ApoE.”
“As a treatment to improve bone healing, the patient could take a pill or an injection to lower ApoE for a short time rather than permanently, and there would be dietary restrictions during treatment. That would be probably a much safer model,” Baht concludes.
[Source(s): Duke University Medical Center, Science Daily]