Researchers at New York's Hospital for Special Surgery (HSS) Research Institute have identified a population of SPP1+ macrophages that appears to drive rheumatoid arthritis through abnormal tissue remodeling rather than classical inflammation, according to a study in Science Translational Medicine. The findings suggest current anti-inflammatory therapies may miss an important disease mechanism responsible for persistent joint damage in some patients.
Rheumatoid arthritis has long been understood primarily as an inflammatory disease, with approved therapies targeting cytokines such as TNF, IL-6, and IL-17, or depleting specific immune cell populations. Yet a substantial proportion of RA patients treated with these agents continue to experience joint damage, suggesting that inflammation alone does not account for the full biology of synovial expansion and erosion.
The HSS team, led by senior author Laura Donlin, PhD, applied spatial transcriptomics to human RA synovial tissue samples to map gene expression within intact tissue architecture. The technique allowed the researchers to map gene expression while preserving tissue architecture, revealing where different cell populations were located and how they interacted. The analysis revealed that SPP1+ macrophages — a subset defined by expression of SPP1, also known as Secreted Phosphoprotein 1 or Osteopontin — were consistently localized within fibrin-rich extracellular matrix niches in the rheumatoid synovium.
The biological pathway identified by the HSS team centers on a fibrin-macrophage-fibroblast axis operating within the synovium. Fibrin, a matrix protein normally deposited transiently during wound repair, accumulates persistently in RA joint tissue. SPP1+ macrophages cluster preferentially within these fibrin-rich regions, where they perform a dual function: processing the fibrin scaffold while generating paracrine signals that drive fibroblast expansion.
Sustaining this macrophage population appears to require IL-6 signaling — a finding with direct relevance to existing RA treatment strategies. IL-6 inhibitors, including tocilizumab and sarilumab, are already approved for RA, and the data raise the possibility that part of their clinical benefit derives from depleting or suppressing this specific macrophage subset, rather than from broad cytokine suppression alone. If confirmed, this could indicate that part of the benefit of IL-6 inhibitors stems from effects on this macrophage population, rather than cytokine suppression alone.
Rather than primarily reflecting classical inflammatory signaling, the process more closely resembles a dysregulated tissue repair program. The tissue expansion driven by SPP1+ macrophages and their fibroblast partners more closely resembles a pro-regenerative or repair program that has been pathologically sustained — a distinction that matters therapeutically, because anti-inflammatory agents are not designed to interrupt this axis directly.