Scientists discover new role of GPNMB protein in heart repair

UCLA researchers have identified the GPNMB protein as a key regulator of heart healing after a heart attack.

Using animal models, it has been shown to originate in the bone marrow immune cells called macrophages secrete GPNMB, which binds to the GPR39 receptor, promoting heart repair. These findings provide a new understanding of how the heart heals itself and may lead to new treatments to improve heart function and prevent the progression of heart failure.

The study was published in Circulatory system research in nature.

Every 40 seconds, someone in the United States has… heart attack— the main cause of heart failure. These cardiac events weaken the heart and cause scarring that reduces the heart’s ability to pump blood effectively. And although this scar tissue initially forms to maintain the heart’s structure, it remains permanently, putting strain on the surviving muscles and ultimately leading to heart failure.

Previous clinical studies have shown that GPNMB, or nonmetastatic melanoma glycoprotein B, is strongly associated with cardiovascular outcomes in people with heart failure. However, it was unclear whether the lack of protein was directly responsible for the development of heart failure after a heart attack.

This important distinction – whether GPNMB is just an associated biomarker or plays a causal role – determines whether the protein can be considered a therapeutic target for future research.

Using mouse models, scientists determined for the first time that GPNMB is not natively expressed in the heart itself, but is produced by inflammatory cells coming from the bone marrow. After a heart attack, macrophages migrate to the site of cardiac injury, where they express GPNMB.

The team performed gene knockouts – inactivation of the GPNMB gene – i bone marrow transplants and observed that mice lacking the GPNMB gene showed dramatically worse outcomes after heart attack, including an increased incidence of heart rupture, a fatal complication also seen in human heart failure patients.

Conversely, mice with normal GPNMB expression that were given an additional dose of circulating GPNMB protein showed improved cardiac function and reduced scarring. Four weeks after a simulated heart attack, 67% of the GPNMB knockout animals showed severe fibrosis, or scarring, compared with only 8% of the control animals.

In addition to identifying GPNMB as a signaling molecule that affects various cell types, researchers found that it binds to GPR39, previously considered an orphan receptor, a receptor whose binding partner is unknown. This interaction triggers a cascade of signals that promote tissue regeneration and reduce scar formation.

Cardiovascular diseases, in which heart failure is a late complication, constitute a serious health problem and cause approximately one third of all deaths worldwide. Despite the prevalence of this disease, there are no treatments available that directly improve the heart’s ability to recover after a heart attack.

New study shows the potential of GPNMB as a therapeutic agent, as well as GPR39 as a target that may reduce scarring, improve heart function and prevent heart failure.

This research may also have broader implications for understanding tissue repair in other organs. Because GPNMB is expressed in many tissues, future research will explore its role in repairing the brain, kidney, and other organs affected by ischemic injury.