A recent study published in Arthritis Research and Therapy has highlighted the emerging role of dipeptidyl peptidase-4 (DPP4) in ankylosing spondylitis (AS), revealing its potential as both a diagnostic biomarker and a therapeutic target. The study demonstrated that soluble DPP4 levels were significantly elevated in the serum and synovial fluid of AS patients, with increased expression particularly noted in mature osteoclasts. Notably, DPP4 presence was pronounced in spinal facet joint tissues, reinforcing its involvement in AS pathology.
To explore the therapeutic potential of DPP4 inhibition, researchers conducted an experimental study using curdlan-injected SKG mice, a widely recognized AS model. Following oral administration of a DPP4 inhibitor, notable improvements were observed, including reduced hind paw thickness, lower arthritis scores, and decreased enthesitis at the ankle. Micro-CT analysis further confirmed a significant reduction in inflammation-induced bone loss. In vivo experiments using curdlan-injected SKG mice confirmed that targeting DPP4 alleviated arthritis, dactylitis, inflammation, and ectopic bone formation in peripheral joints. In vitro findings further supported these outcomes, showing that DPP4 inhibition reduced TRAP-positive osteoclast formation and NFATc1 expression, alongside decreased phos-Y527 SRC and phos-p38 expression.
DPP4 is a widely expressed, multifunctional serine peptidase that exists both as a membrane-bound cell surface protein and in soluble form in plasma. Its inflammatory role is linked to increased levels of pro-inflammatory cytokines such as IL-6 and IL-8 through activation of the MARK and NF-κB signaling pathways. DPP4 is also recognized as an adipokine, contributing to obesity and insulin resistance, both of which are implicated in osteoporosis development.
Previous research by Yu et al. identified serum DPP4 as a potential biomarker for assessing disease activity and treatment response in rheumatoid arthritis (RA). The study’s proteomic analysis of RA patients before and after 24 weeks of treatment demonstrated DPP4 as a reliable marker for monitoring disease progression and optimizing therapy. Moreover, DPP4 inhibition has been shown to suppress CXCL10 and CXCR3 expression, potentially reducing RA symptoms.
This latest study highlights the therapeutic potential of DPP4 inhibitors in reducing inflammation-driven ectopic bone formation in AS. Elevated DPP4 levels and increased expression in serum, synovial fluid, and facet joint tissues of AS patients suggest its significant role in disease progression. The presence of DPP4 in mature osteoclasts further underscores its impact on inflammation-mediated bone formation.
These findings suggest that DPP4 plays a crucial role in AS pathogenesis by driving inflammation-mediated bone formation. Targeting DPP4 may offer a promising therapeutic approach to improving disease outcomes and enhancing the quality of life for AS patients. This research not only underscores the diagnostic potential of DPP4 but also opens new avenues for effective AS treatment strategies.
References
- Lee SH, Lee KH, Kim D, Jeon C, Whangbo M, Jo HR, et al. Targeting osteoclast-derived DPP4 alleviates inflammation-mediated ectopic bone formation in ankylosing spondylitis. Arthritis Res Ther. 2025 Feb 25;27(1):40.
- Yu J, Hu C, Dai Z, Xu J, Zhang L, Deng H, et al. Dipeptidyl peptidase 4 as a potential serum biomarker for disease activity and treatment response in rheumatoid arthritis. Int Immunopharmacol. 2023 Jun;119:110203.