Dickkopf-1 in rheumatoid arthritis: Mechanistic insights, imaging associations, and emerging therapeutic strategies

Abstract

Rheumatoid arthritis (RA) is a persistent autoimmune disease characterized by synovial inflammation, progressive joint destruction, and functional disability. A soluble canonical Wnt/β-catenin pathway inhibitor called dickkopf-1 (DKK-1) has become a key regulator of pathological bone remodeling in RA. DKK-1 uncouples bone formation from resorption by antagonizing Wnt signaling through degradation of lipoprotein receptor-related protein 5/6. This suppresses osteoblastogenesis, reducing osteoprotegerin expression, and enhances RANKL-mediated osteoclastogenesis, thereby promoting joint and structural erosion. A systematic literature review of preclinical and clinical papers was conducted to evaluate the DKK-1-mediated molecular pathogenesis of RA. Evidence was synthesized regarding the associations of DKK-1 with inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), autoantibodies (rheumatoid factor and anti-citrullinated protein antibodies), disease activity (Disease Activity Score 28 [DAS28]), and radiographic erosion measures. The modulatory role was examined by looking at genetic polymorphisms (rs1896367, rs1896368). Imaging modalities, such as power Doppler ultrasound, radiography and magnetic resonance imaging, were evaluated in the context of their complementary relationship with DKK-1 levels. The therapeutic approaches to DKK-1, such as preclinical blockade models and indirect control with tumor necrosis factor-alpha inhibitors were critically analyzed. High serum and synovial DKK-1 levels were significantly associated with inflammatory indices, autoantibody titers, disease activity, and structural damage on imaging. The polymorphism at the rs1896367 locus predisposed patients to aggressive erosive disease, and the rs1896368 polymorphism was somewhat protective. Multimodal imaging showed complementary correlations, which made DKK-1 an ideal biomarker for early detection and treatment-monitoring. Preclinical DKK-1 blockade rescued erosive phenotypes, stimulated osteoblast activity and prevented the erosion development, although inflammation persisted. Tumor necrosis factor-alpha inhibition indirectly suppressed DKK-1, confirming that it is a useful pharmacodynamic marker. DKK-1 is a multidimensional biomarker that combines molecular genetics, immunopathology and imaging in RA. Although promising as a therapy, DKK-1 as a precision rheumatology target needs to overcome various translational challenges, such as ectopic ossification, risk of joint fusion, assay variability, lack of standardized thresholds, and large-scale clinical trials. The available studies and clinical trials demonstrate considerable heterogeneity, likely attributable to a lack of assay standardization, differences in reported units for DKK-1 concentrations, and preclinical factors, as biomarkers like RANKL and osteoprotegerin are sensitive to storage conditions. DKK-1 levels are also influenced by disease stage and duration, with higher concentrations observed in early RA, as well as by treatment status, which is associated with significantly reduced DKK-1 levels. Additional sources of variability include genetic differences among patients, higher DKK-1 concentrations within the synovial compartment compared with serum, and more rapid clearance from serum than from synovial tissue. Although DKK-1 is a promising biomarker for early RA, these challenges must be addressed before it can be incorporated into routine clinical practice. Future studies should focus on establishing the safety, standardization, and population-based reference ranges of DKK-1. In India, research on DKK-1 remains limited, and large-scale clinical trials have not yet been conducted. Future investigation could help validate its clinical utility and facilitate its translation into broader clinical studies and eventual clinical practice.

Keywords: Dickkopf-1; Rheumatoid arthritis; Wnt/β-catenin; Osteoprotegerin; RANKL; Osteoclastogenesis

Core Tip: Dickkopf-1 (DKK-1) is a key regulator of bone remodeling in rheumatoid arthritis, driving erosion by inhibiting Wnt signaling, suppressing osteoblasts, and enhancing RANKL-mediated osteoclastogenesis. Elevated DKK-1 correlates with inflammation, autoantibodies, disease activity, and imaging indices, while genetic variants modulate risk. Though blockade shows therapeutic promise, safety concerns and assay variability remain. DKK-1 offers a multidimensional biomarker for prognosis, monitoring, and precision-targeted therapy in rheumatoid arthritis.