Although poorly understood, injury and illness are known to spark the transition of heart cells into bone. Breaking research shows how this process may occur and investigates interventions that might help prevent it.
Under normal conditions, tissues outside of bones do not calcify.
However, as we age and in individuals with diabetes and kidney disease, calcification can appear in other tissue types.
This mineralization has been observed in the blood vessels, kidney, and heart. When it occurs in the heart, it can disrupt the normal transmission of electrical signals.
This can have a serious, detrimental effect on the workings of organs and, currently, there are no treatments that can reverse or reduce this chemical change.
In fact, calcification of the heart muscle is one of the most common underlying causes of heart blocks – a condition where the heart beats abnormally slowly.
Although mineralization has been observed in a number of medical situations, the mechanisms behind it have not been investigated at length, and many questions about its inner workings remain unknown.
Researchers from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California-Los Angeles, set out to look at this mysterious area of medicine in more detail.
“Heart calcification has been understudied and underreported, We asked the question, ‘What are the cells in the heart that cause calcification?’ and given the strong association between tissue injury, fibrosis, and calcification, we hypothesized that maybe it is cardiac fibroblasts [cells that give rise to scar tissue after injury] that are contributing to the calcification process.”
Senior author Arjun Deb
In order to understand this calcification within heart tissue, Deb and his co-authors designed a way to observe cardiac fibroblasts using genetic tagging technology; they watched these cells in mice as they morphed into bone-forming, osteoblast-like cells following an injury.
Next, to further investigate the function of these cells, they took the cardiac fibroblasts from the injured mice and transplanted them under the skin of healthy mice. As predicted, soft-tissue in the region calcified in a similar way.
Additionally, the team demonstrated that human cardiac fibroblasts were also capable of forming calcium deposits in a laboratory dish.
Deb’s findings, published this week in Cell Stem Cell, go some way to describe the way in which tissue can turn into a bone-like substance. The next, and perhaps more pressing, problem is how these changes might be reversed or, at least, slowed.
The team decided to study the influence of a small molecule, known as ENPP1, on the calcification process. This enzyme is known to be overexpressed by cardiac fibroblasts following an injury, making it a prime target for further investigation.
By injecting a range of small molecules that might disrupt ENPP1 (prior to injury) they witnessed a 50 percent decrease or more in the calcification process.
In particular, injection of the drug etidronate saw the most promising interaction – it was 100 percent successful, with no measurable calcification following injury. Etidronate is normally prescribed for individuals with Paget’s disease, a condition where the bone generation process is disorganized.
Because this sphere of physiology is not well-studied, this study marks a strong starting point for future research. Deb says: “We now want to see whether this is a common pathway to calcification regardless of etiology and if what we found can be broadly applied to tissues across the body.”
Already, the team has begun investigating the use of other small molecules to reduce or prevent calcification in blood vessels. Also, because ENPP1 was only effective if it was delivered before the injury, the hunt is on for molecules that can be effective when injected following an injury.