Elevated Serum Dickkopf-1 is a Biomarker for Bone Erosion in Patients with Psoriatic Arthritis
Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects individuals with psoriasis, leading to joint inflammation, bone erosion, and new bone formation. Despite its significant impact on patients’ quality of life, the pathogenesis of PsA remains poorly understood, and there is a lack of specific biomarkers to distinguish it from other inflammatory arthritis conditions. Recent research has focused on the role of Dickkopf-1 (Dkk-1), a key inhibitor of the Wnt signaling pathway, in bone remodeling and inflammation. This study aimed to investigate the serum levels of Dkk-1 in PsA patients and explore its association with bone erosion, providing insights into the mechanisms underlying PsA and potential therapeutic targets.
Introduction
Psoriatic arthritis is a complex autoimmune disorder characterized by peripheral arthritis, spondylitis, enthesitis, dactylitis, and skin psoriasis. The disease is marked by progressive bone destruction and aberrant new bone formation, which contribute to joint damage and disability. Laboratory markers for PsA are non-specific, and the absence of specific autoantibodies complicates its differentiation from other inflammatory arthritis conditions, such as rheumatoid arthritis (RA). Elevated inflammatory markers, including white blood cells (WBCs), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), are common but not specific to PsA.
The Wnt/β-catenin signaling pathway plays a crucial role in regulating osteoblast proliferation, differentiation, and bone formation. Dkk-1, a natural inhibitor of this pathway, promotes the degradation of β-catenin, leading to reduced osteoblast activity and increased osteoclast-mediated bone resorption. This imbalance results in bone erosion, a hallmark of inflammatory arthritis. While Dkk-1 has been implicated in bone erosion in RA, its role in PsA remains controversial. This study sought to clarify the relationship between Dkk-1 levels and bone erosion in PsA patients by comparing serum Dkk-1 levels in PsA patients, RA patients, and healthy controls (HCs).
Methods
The study enrolled 69 PsA patients, 39 RA patients, and 21 HCs. All PsA patients met the Classification of Psoriatic Arthritis (CASPAR) criteria, while RA patients fulfilled the revised American College of Rheumatology criteria. Serum samples were collected and stored at -70°C until analysis. Dkk-1 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit, and clinical and laboratory data, including swollen joint count, tender joint count, and complement components, were collected from medical records. Radiographic assessments of joint erosion and new bone formation were performed using the modified Sharp-van der Heijde method.
Results
The study found that serum Dkk-1 levels were significantly elevated in PsA patients compared to RA patients and HCs. Specifically, Dkk-1 was elevated in 68.1% of PsA patients, 46.2% of RA patients, and only 9.5% of HCs. The mean serum Dkk-1 concentration in PsA patients was 9.269 ng/mL, compared to 7.862 ng/mL in RA patients and 6.250 ng/mL in HCs. These findings suggest that Dkk-1 may play a role in the pathogenesis of PsA.
Further analysis revealed that elevated Dkk-1 levels were associated with increased disease activity in PsA patients. Patients with elevated Dkk-1 had higher swollen joint counts and lower levels of complement components C3 and C4, indicating a more severe inflammatory state. Radiographic assessments showed that PsA patients with elevated Dkk-1 levels had a higher prevalence of sacroiliitis, radiographic axial disease (RAD), and bone erosion compared to those with normal Dkk-1 levels. The Sharp score, which quantifies joint damage, was also significantly higher in patients with elevated Dkk-1.
Logistic regression analysis identified elevated Dkk-1 as an independent risk factor for bone erosion in PsA patients, with an odds ratio of 4.440 (95% confidence interval: 1.246–15.817, P = 0.021). This finding underscores the potential of Dkk-1 as a biomarker for bone erosion in PsA.
Discussion
The study’s findings highlight the role of Dkk-1 in the pathogenesis of PsA, particularly in bone erosion. Elevated serum Dkk-1 levels were associated with increased disease activity, radiographic damage, and bone erosion in PsA patients. These results align with previous studies that have implicated Dkk-1 in bone remodeling and inflammation in other forms of arthritis, such as RA and ankylosing spondylitis.
Dkk-1 inhibits the Wnt/β-catenin signaling pathway, which is essential for osteoblast proliferation and bone formation. By promoting the degradation of β-catenin, Dkk-1 shifts the balance toward bone resorption, leading to bone erosion. This mechanism may explain the observed association between elevated Dkk-1 levels and bone erosion in PsA patients. Additionally, Dkk-1’s role in inflammation may contribute to the increased disease activity seen in patients with elevated Dkk-1 levels.
The study also found that PsA patients with elevated Dkk-1 had a higher prevalence of sacroiliitis and RAD, suggesting that Dkk-1 may be involved in axial involvement in PsA. This finding is consistent with previous research in ankylosing spondylitis, where elevated Dkk-1 levels were associated with radiographic damage.
Despite these significant findings, the study has several limitations. The sample size was relatively small, and all patients were recruited from a single center, which may limit the generalizability of the results. Additionally, the retrospective design of the study precluded the collection of longitudinal data, such as psoriasis area and severity index (PASI) scores. Future studies with larger, multicenter cohorts and prospective designs are needed to confirm these findings and explore the potential of Dkk-1 as a therapeutic target in PsA.
Conclusion
This study demonstrates that serum Dkk-1 levels are significantly elevated in PsA patients and are associated with increased disease activity, radiographic damage, and bone erosion. These findings suggest that Dkk-1 may play a key role in the pathogenesis of PsA and could serve as a biomarker for bone erosion. Further research is needed to explore the mechanisms underlying Dkk-1’s role in PsA and to evaluate its potential as a therapeutic target. Understanding the role of Dkk-1 in PsA may provide new insights into the disease’s pathogenesis and lead to the development of novel treatments aimed at preventing bone erosion and improving patient outcomes.
doi.org/10.1097/CM9.0000000000001612
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