APRIL 30, 2025 – A new study led by researchers at Hospital for Special Surgery (HSS) suggests that currently available therapies may help control chronic muscle inflammation in Duchenne muscular dystrophy (DMD), a severe condition that leads to muscle weakness and premature death. The study, published in PNAS, identifies new mechanisms that drive chronic muscle inflammation in a disease model of a DMD. Researchers believe that targeting these mechanisms with existing therapies could help reduce inflammation and support muscle function.
DMD is caused by a mutation in the dystrophin gene, which produces a large protein essential for stabilizing muscle cell membranes that help protect muscle fibers. Without dystrophin, muscle damage occurs and builds, leading to persistent inflammation and fibrosis (scarring). The condition primarily affects boys—occurring in about 1 in 5,000 live male births—and leads to premature death due to respiratory and cardiac muscle weakness. There is currently no cure.
The research team focused on monocytes (a type of white blood cell) that travel through the blood stream to infiltrate diseased muscles and become inflammatory macrophages, which promote muscle damage and scarring. They previously discovered that blocking monocyte recruitment from the blood circulation temporarily decreased macrophage accumulation, reduced scarring, and improved muscle function in a disease model of DMD.
“The benefit is transient,” says Lan Zhou, MD, Neurologist-in-Chief at HSS and senior author of the study. “Inhibiting macrophage infiltration alone is not sufficient for controlling chronic muscle inflammation, which contributes to muscle damage and fibrosis,”
To uncover additional factors driving macrophage accumulation, the investigators used state-of-the-art technologies, including single-cell RNA sequencing analysis and lineage tracing, to determine the key mechanism that is responsible for fueling chronic inflammation after macrophage infiltration is blocked.
According to the newly published research, Dr. Zhou and her colleagues discovered that mesenchymal stromal cells (a type of stem cell) in muscle tissue called fibro/adipogenic progenitors (FAPs) produce cytokines or growth factors known as colony-stimulating factor (CSF-1). CSF-1 stimulates resident macrophages in skeletal muscles to proliferate and accumulate, which contributes to chronic inflammation and muscle dystrophy. The findings uncover a new function of FAPs that fuels chronic inflammation and promotes DMD disease progression.
The researchers concluded that it might be equally important to suppress resident macrophage expansion and activation in addition to inhibiting macrophage infiltration.
“That means that in order to control chronic muscle inflammation and improve muscle function in patients with DMD, both macrophages and FAPs may need to be targeted,” explains Dr. Zhou.
As a next step, Dr. Zhou and her team are planning to study the safety and efficacy of a combination therapy using two existing drugs developed for other conditions. One is used to treat chronic inflammation by suppressing macrophage infiltration. The other is a CSF-1 inhibitor used to treat a type of joint tumor that consists of many macrophages due to excessive CSF-1.
Limited treatment options exist for patients with DMD. Researchers continue to refine gene therapy and cell therapy approaches for DMD, which have so far shown limited success in clinical trials.
“Experts in the field believe that patients will ultimately require a combination of treatment approaches, not only to correct genetic defects, but also to improve the diseased muscle tissue environment, making the gene and cell therapies more effective,” says Dr. Zhou. “Targeted drugs could be used to treat the inflammatory and fibrotic tissue environment so that healthy genes or cells can be efficiently engrafted, survive, and function.”
HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 15th consecutive year), No. 3 in rheumatology by U.S. News & World Report (2024-2025), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2024-2025). In a survey of medical professionals in more than 20 countries by Newsweek, HSS is ranked world #1 in orthopedics for a fifth consecutive year (2025). Founded in 1863, the Hospital has the lowest readmission rates in the nation for orthopedics, and among the lowest infection and complication rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. In addition, more than 200 HSS clinical investigators are working to improve patient outcomes through better ways to prevent, diagnose, and treat orthopedic, rheumatic and musculoskeletal diseases. The HSS Innovation Institute works to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 165 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.
