In a groundbreaking study published in Arthritis & Rheumatology, researchers have identified a promising therapeutic target in the CD13/Aminopeptidase N (APN) pathway, offering new hope for patients with systemic sclerosis (SSc). The study reveals that soluble CD13 (sCD13) plays a pivotal role in promoting skin fibrosis by interacting with the bradykinin receptor B1 (B1R), a finding that could pave the way for novel treatment strategies.
Analysis of skin biopsies from patients with diffuse cutaneous SSc (dcSSc) revealed significantly elevated expression of CD13, B1R, and matrix metalloproteinase 14 (MMP14). Single-cell RNA sequencing further identified high BDKRB1 expression in COL8A1-positive myofibroblasts, a unique cell population exclusive to SSc. Notably, TGF-β was shown to induce both BDKRB1 expression and sCD13 production in dcSSc skin fibroblasts. Further functional studies demonstrated that exposure to sCD13 drives fibrotic gene expression, cell proliferation, migration, and collagen contraction—key mechanisms in fibrosis progression. These effects were attenuated by B1R antagonism, highlighting the therapeutic potential of blocking this pathway.
To validate these findings, researchers conducted in vivo experiments in mouse models. Mice deficient in CD13 or Bdkrb1 exhibited resistance to bleomycin-induced skin fibrosis and inflammation, further confirming the fibrogenic role of the sCD13-B1R axis. Additionally, pharmacological inhibition of B1R significantly reduced fibrosis, reinforcing its potential as a viable therapeutic target.
Originally identified as a myeloid cell marker, CD13/APN is a widely expressed metallopeptidase involved in immune regulation, angiogenesis, and inflammation. CD13 is cleaved by MMP14, generating soluble CD13, which serves as a chemoattractant for monocytes, T cells, fibroblasts, and endothelial cells. This study provides concrete evidence that sCD13 plays a central role in SSc pathogenesis, making it a compelling target for future therapies.
Morgan et al. previously reported elevated CD13 levels in rheumatoid arthritis (RA) synovial fluid, suggesting that CD13-mediated immune cell recruitment contributes to chronic inflammation in autoimmune diseases beyond SSc. This highlights its broader implications in immune-driven fibrosis and inflammation.
This finding represents a major advancement in scleroderma research, pinpointing the sCD13-B1R signaling axis as a potential cornerstone for future SSc treatments. By targeting CD13/B1R interactions, researchers hope to develop novel antifibrotic therapies that could slow disease progression and improve patient outcomes. With further clinical validation, this approach could revolutionize systemic sclerosis treatment, offering new hope for millions affected by this debilitating autoimmune condition.
References
- Muraoka S, Brodie WD, Mattichak MN, Gurrea-Rubio M, Ikari Y, Foster C, et al. Targeting CD13/Aminopeptidase N as a Novel Therapeutic Approach for Scleroderma Fibrosis. Arthritis Rheumatol. 2025 Jan;77(1):80-91.
- Morgan R, Endres J, Behbahani-Nejad N, Phillips K, Ruth JH, Friday SC, et al. Expression and function of aminopeptidase N/CD13 produced by fibroblast-like synoviocytes in rheumatoid arthritis: role of CD13 in chemotaxis of cytokine-activated T cells independent of enzymatic activity. Arthritis Rheumatol. 2015 Jan;67(1):74-85.