Researchers at Hospital for Special Surgery (HSS) have identified a specialized population of immune cells that play a central role in driving abnormal tissue growth in rheumatoid arthritis (RA), offering new insight into disease progression and potential treatment strategies.
The study, published in Science Translational Medicine, reveals that a subset of immune cells known as SPP1ʰⁱ macrophages work in tandem with structural cells and protein scaffolds to promote excessive tissue expansion in the joints of patients with RA.
RA is a chronic autoimmune disease that causes inflammation of the synovium—the tissue lining the joints—leading to pain, swelling, and eventual damage to cartilage and bone. While current therapies largely focus on controlling inflammation, the mechanisms that drive the abnormal growth of synovial tissue—and its invasive portion, known as pannus, which erodes cartilage and bone—have remained poorly understood.
A New Model of Tissue Growth in RA
Using advanced spatial transcriptomics to analyze human tissue samples, the HSS research team discovered that SPP1ʰⁱ macrophages cluster within fibrin-rich niches in the synovium. Fibrin, a protein typically involved in blood clotting and wound healing, appears to act as a temporary scaffold that supports new tissue formation.
Within these niches, the macrophages were found to:
- break down fibrin scaffolds through enzymatic activity and cellular uptake;
- stimulate nearby fibroblasts, key structural cells, to proliferate; and
- promote tissue remodeling and expansion independent of traditional inflammatory pathways.
“This work suggests that rheumatoid arthritis is not only driven by inflammation, but also by dysregulated tissue repair processes,” said Laura Donlin, PhD, senior author and scientist at the HSS Research Institute. “We are seeing a coordinated interaction between immune cells, structural cells, and the extracellular matrix that fuels abnormal growth.”
Beyond Fibrosis: A Distinct Pathway
Interestingly, while SPP1ʰⁱ macrophages resemble cells involved in fibrotic diseases such as lung or liver fibrosis, the RA tissue environment lacks the dense collagen buildup characteristic of fibrosis. Instead, the researchers describe this process as “pro-generative” tissue remodeling, more closely resembling wound healing gone awry.
Therapeutic Implications
The findings also suggest that targeting SPP1ʰⁱ macrophages and their signaling pathways could represent a new therapeutic approach. The study highlights the role of IL-6 signaling in sustaining these cells, offering further insight into why IL-6–targeting therapies, already used in RA, may be particularly effective in certain patient populations.
“Current treatments focus on suppressing inflammation, but our findings point to additional pathways that drive disease progression,” said Dr. Donlin. “Targeting these tissue remodeling processes could open the door to more precise and effective therapies.”
Broader Impact
The study’s findings may extend beyond RA. Similar immune cell populations and fibrin-based remodeling processes have been implicated in other conditions, including interstitial lung disease, lupus, cancer, and traumatic injury, suggesting a broader role for this pathway in human disease.
About HSS
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 16th consecutive year), No. 3 in rheumatology by U.S. News & World Report (2025-2026), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2025-2026). 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.
View source version on businesswire.com: https://www.businesswire.com/news/home/20260625124624/en/
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