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.

Key Words: 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.

INTRODUCTION

Rheumatoid arthritis (RA) is a persistent autoimmune disease that manifests itself in the peripheral polyarthritis of synovial joints, resulting in joint destruction to the extent of deformity. It is prevalent in almost 0.5%-1% of the global adult population, with women and the elderly more commonly affected[1,2].

An imbalance between bone-forming and bone-resorbing activity within inflamed joints is causative in RA. Dickkopf-1 (DKK-1) is a soluble endogenous inhibitor of the canonical Wnt/β-catenin signaling pathway and has been identified as a molecular mediator of this imbalance[3]. DKK-1 induces erosion that characterizes active RA, through the inhibition of osteoblast differentiation and indirect promotion of osteoclast activity[1,4-7].

DKK-1 levels in serum and synovial fluid have been explored as a diagnostic/prognostic biomarker and a potential therapeutic target of RA. There is evidence that DKK-1 levels are aligned with disease activity, severity of synovitis, and radiographic progression[2,8-10]. Diversity in assay platforms, overlap with other inflammatory diseases, and lack of standard cutoff values have restricted its use in normal clinical practice[11,12].

This narrative review summarizes and critically evaluates the existing literature on DKK-1 in RA, primarily in terms of its biological activity, relationship with disease activity and structural outcomes, its possible use in RA diagnosis and prognosis, and the limitations that need to be overcome before it can be clinically used. Taken together, we are assessing the possibility of DKK-1 as a reliable biomarker and commenting on the future perspectives of research and treatment creation. This review highlights disease progression with the use of DKK-1 and imaging modalities. The review also discusses the effectiveness of DKK-1 as a biomarker. We also summarize preclinical studies that, despite showing the effectiveness of DKK-1, also demonstrate the safety considerations of pathologic bone fusion and possible cancer development.

METHODOLOGY

The review aimed to approach DKK-1 through its biology, pathophysiology, polymorphisms, its use as a marker in RA, correlation with disease activity through predicting radiographic progression, its treatment response as a pharmacodynamic marker, and the limitations and safety considerations. The relevant literature was selected across PubMed, Scopus, Web of Science, and EMBASE. After the selection of literature, each reference was exported to a reference management software. Relevant studies were identified against the inclusion criteria.

Inclusion criteria

Systematic reviews, narrative reviews, clinical and preclinical studies, and animal studies investigating DKK-1 in orthopedic conditions were included. Eligible articles were published within the past 25 years and involved either healthy individuals or patients with RA. Studies were required to evaluate the role of DKK-1 as a biomarker. Literature searches were performed using PubMed, Google Scholar, and Scopus. The following keywords were used: Dickkopf-1, serum DKK-1 levels, rheumatoid arthritis, genetic variation of DKK-1, biomarkers in RA, imaging in RA.

A narrative synthesis approach was used to organize and analyze the evidence under the following themes: DKK-1 biology, pathophysiology, polymorphisms, its role as a marker in RA, its correlation with disease activity and radiographic progression, its utility as a pharmacodynamic marker of treatment response, and its limitations and safety considerations. Comparisons between DKK-1 and various imaging modalities were summarized in tabular form, and associations between DKK-1 and other inflammatory factors were also evaluated.

WNT/Β-CATENIN SIGNALING IN BONE HOMEOSTASIS

The canonical Wnt/β-catenin signaling pathway is a regulator of skeletal development and bone homeostasis[13,14]. Wnt ligand functions include stimulation of osteoblastogenesis, enhancement of bone matrix production, and inhibition of osteoclast-mediated bone resorption[15-18].

Pathway activation

When the Wnt signaling pathway is in an active state, its ligands bind to Frizzled receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors[19,20]. This double binding leads to the recruitment of the scaffold protein Dishevelled and triggers phosphorylation of the LRP5/6 cytoplasmic tail[21]. This phosphorylation inactivates the destruction complex, consisting of Axin, APC, and GSK-3b[15,19,22,23]. With the destruction complex inhibited, newly synthesized β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it binds with TCF/LEF transcription factors and activates Wnt target genes. Among these, c-MYC and cyclin D1 promote osteoblast proliferation, differentiation, and bone matrix deposition[24-28].

When the Wnt signaling pathway is inactive, the destruction complex remains active, therefore leading to the phosphorylation of β-catenin, leading to its ubiquitination and proteasomal degradation[4,29]. The net result is reduced nuclear β-catenin and reduced transcription of anabolic genes in the bone[15,28].

Wnt-mediated anti-osteoclastic effects

Along with direct anabolic effects on osteoblasts, canonical Wnt signaling has an important anti-resorptive action through its modulation of the RANK-RANKL-osteoprotegerin (OPG) axis[25,26]. Wnt signaling in mature osteoblasts induces the OPG synthesis, which acts as a decoy receptor for RANKL[25,26,30]. By binding to RANKL, OPG prevents RANKL from engaging with RANK on osteoclast precursors, therefore suppressing osteoclast differentiation and bone resorption[31,32]. This is a crucial link between the anabolic and anti-resorptive functions of bone metabolism, and its imbalance is the main cause of joint impairment in RA[29,33].

PATHOPHYSIOLOGY OF DKK-1 IN RA

DKK-1 is an endogenous and soluble Wnt inhibitor that causes an imbalance in the Wnt signaling at the level of LRP5/6 co-receptors[34]. It binds with high affinity to LRP5/6, which progressively leads to their internalization and degradation. This prevents the formation of functional Wnt-Frizzled-LRP5/6 signaling complexes, therefore effectively stopping the anabolic Wnt response[5]. In RA, synovial fibroblasts, macrophages, and osteoblasts within the inflamed joint may express increased DKK-1 levels under the influence of tumor necrosis factor-alpha (TNF-α) and other pro-inflammatory cytokines, therefore reaching high local concentrations that suppress bone repair[2,35].

The downstream consequences are dual. Initially, the suppressed Wnt signaling reduces OPG expression in osteoblasts[36]. This shifts the OPG:RANKL ratio toward RANKL excess, increasing osteoclast recruitment, differentiation, and activity[37-39]. Next, the reduced β-catenin-dependent transcription reduces osteoblast survival and function, making bone repair harder. Together, these mechanisms produce a state of bone remodeling where resorption is more than formation, leading to periarticular erosions in RA[29,35].

This has been studied in mouse models of collagen-induced arthritis (CIA), where circulating DKK-1 levels correlated with the severity of bone disfigurement. DKK-1 also increased the number of myeloid-derived suppressor cells. These cells are capable of differentiating into osteoclasts, therefore promoting bone resorption[40]. In the synovial fibroblasts from patients diagnosed with very early RA (eRA) (disease duration < 3 months), high DKK-1 levels increased lymphocyte adhesion in vitro. This suggests that DKK-1 causes structural damage before clinical symptoms become chronic[41,42]. The mechanism of DKK-1 in the joint milieu is depicted in Figure 1.

Figure 1 Mechanism of dickkopf-1 in joint milieu. Figure 1 is drawn in Biorender.com. DKK-1: Dickkopf-1; TNF-α: Tumor necrosis factor-alpha; OPG: Osteoprotegerin.

GENETIC POLYMORPHISMS OF DKK-1 IN RA

Genetic variants within the DKK-1 locus modulate both its protein expression level and the severity of structural damage in RA. Two single-nucleotide polymorphisms have received particular attention: (1) Rs1896367; and (2) Rs1896368[43-45].

Rs1896367: Risk variant for structural damage

Aggressive structural damage is linked with the rs1896367 variant, especially in the feet. Carriers exhibited a higher level of bone erosion (P = 0.026), increased joint space narrowing (JSN) (P = 0.005), and higher Sharp-van der Heijde Scores (SHS) (P = 0.016) than non-carriers in a Colombian cross-sectional cohort of patients with eRA[46-48]. It is worth noting that a Simple Erosion Narrowing Score (SENS) over 6 in this group had only a probability of 0.1% of occurrence by chance, meaning that there was a strong genetic-structural relationship[8,49,50]. Homozygous carriers of rs1896367 also showed an association with periodontal disease (P = 0.009), which further expanded the implications of this polymorphism to systemic phenotypes[51,52].

Rs1896368: Protective variant

On the other hand, lower radiographic damage is linked to the rs1896368 variant. Carriers exhibit lower risk of radiographic progression (P = 0.05), reduced JSN in hands and feet (P = 0.026); there were no reports of cases with SENS > 6 in available cohorts (P < 0.001)[43,46,53]. These findings collectively indicate that genetic variation in DKK-1 can serve as a biological modifier of structural outcomes in RA, with clear potential relevance to patient stratification in precision medicine frameworks[43].

DKK-1 AS A BIOMARKER IN RA

Serum levels: Comparative and quantitative data

Review of previous literature identified a systematic review and meta-analysis of nine studies (1305 RA patients vs 504 healthy controls) that confirmed elevated serum DKK-1 levels in RA, with a pooled standardized mean difference of 0.79[8,9]. The reported serum DKK-1 concentrations ranged from 66 ng/mL to 453 ng/mL in RA patients compared with 15-87 ng/mL in healthy controls[2,8,54]. Similarly, one study found mean DKK-1 levels of 5888 ± 1868 pg/mL in RA patients vs 1524 ± 430 pg/mL in controls[11]. In postmenopausal RA women, DKK-1 levels were higher than those of controls and were inversely related to bone mineral density loss, similar to systemic skeletal disease[2,54].

CORRELATION WITH DISEASE ACTIVITY AND INFLAMMATORY MARKERS

DKK-1 expression correlates with indices of disease activity and systemic inflammation. A study conducted at Zagazig University reported a very strong positive correlation with composite indices like disease activity score 28 (DAS-28), C-reactive protein (CRP), and erythrocyte sedimentation rate. The high positive value is likely due to a small sample size. These results must be interpreted with caution and not be generalized across populations. Another variability in correlation arose when patients at different disease stages were exposed to the same treatment modality. Key findings from published studies are summarized in Table 1[8,9,11,42,54-61].

Table 1 Correlations between serum dickkopf-1 and indices of disease activity, inflammation, and autoimmunity in rheumatoid arthritis.

Parameter	Correlation finding	Ref.
DKK-1 vs DAS-28	r = 0.960 (very strong positive)	Ali et al[9], Juarez et al[54], Fang et al[55]
DKK-1 vs DAS-28 (Spearman)	rho = 0.75	Abdulaziz et al[56], Coras et al[57]
DKK-1 vs CRP	r = 0.640 (significant positive)	Santos et al[11], Sadek et al[42], Coras et al[57]
DKK-1 vs ESR	r = 0.498 (significant positive)	Santos et al[11], Sadek et al[42], Coras et al[57]
DKK-1 vs RF	r = 0.473 (significant positive)	Ali et al[9], Santos et al[11]
DKK-1 vs Anti-CRP antibodies	r = 0.478 (significant positive)	Ali et al[9], Santos et al[11]
DKK-1 vs RA	r = 0.876 (very strong positive)	Santos et al[11]
DKK-1 vs steinbrocker functional grade	Higher levels in class III (4689-8092 pg/mL)	Ma et al[8], Ali et al[9], Sadek et al[42], Juarez et al[54]
Diagnostic cut-off	2726.97 pg/mL; sensitivity of 98.18%, specificity of 100% for active RA by DAS-28	Procaccia et al[58], Bagherzadeh-Fard et al[59], McWilliams et al[60], Pertsinidou et al[61]

DAS-28: Disease activity score 28; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; RA: Rheumatoid arthritis; RF: Rheumatoid factor.

PREDICTIVE VALUE FOR RADIOGRAPHIC PROGRESSION

Baseline circulating DKK-1 levels predicted radiographic progression, specifically erosion development, in eRA patients receiving etanercept, independent of CRP and disease activity scores[2]. Furthermore, the DKK-1/R-spondin 1 (RSPO1) ratio was more strongly affiliated with erosive disease and the rate of radiographic progression than DKK-1 alone, as RSPO1 is a potent Wnt pathway agonist that functionally opposes DKK-1. Thus, this ratio method may be more precise in reflecting pathway-level dysregulation than either of the two molecules alone[62,63]. DKK-1 levels in the cross-sectional RA cohort correlated with erosion score and negatively correlated with bone mineral density, which supports its dual participation in the process of periarticular bone loss and systemic bone weakening[64-67].

RESPONSE TO TREATMENT AS A PHARMACODYNAMIC MARKER

TNF-α blocker and interleukin-1 (IL-1) receptor antagonist treatment decrease serum DKK-1 levels, suggesting that DKK-1 is a dynamically regulated protein in response to anti-inflammatory therapy. Radiographic outcome has been suggested to be dependent on DKK-1 changes in biological therapy, suggesting that it may serve as a pharmacodynamic biomarker of anti-erosiveness[68-70]. Notably, not all cohorts with strict therapeutic control have shown any significant changes in DKK-1 among the biologic classes, suggesting that treatment intensity and disease stage bring heterogeneity to the pharmacodynamic signal[53,54].

LIMITATIONS OF CURRENT BIOMARKER EVIDENCE

There is heterogeneity in findings across disease activity scores (DAS-28, CDAI, SDAI, RAPID3), which is a limitation that is repeatedly observed in studies of DKK-1, appearing stronger in early and active RA than in long-standing disease[8,71]. The predominance of cross-sectional study designs in studying DKK-1 levels prevents us from providing a definitive etiology. Large-scale multicenter longitudinal studies validating DKK-1 as a predictor of future erosive damage remain limited[9,12,54].

Reported thresholds (e.g., approximately 2726.97 pg/mL) show high sensitivity/specificity in isolated studies, though there is a lack of universal validation across populations, labs, and different disease stages[11,12]. The use of different ELISA kits with different antibodies and experimental standards gives different values. For DKK-1 concentrations, many reports use different units (pg/mL vs ng/mL). These factors limit cross-study comparisons[9,66,72,73].

Serum DKK-1 is not always consistent with joint-specific Wnt signaling. Local TNF-α induces the production of DKK-1 in synovial fibroblasts, generating high local concentrations in synovial fluid that may be independent of the circulating signal. In addition, the clearance of DKK-1 from serum is faster than from synovial fluid, thus making comparisons between compartments unreliable[12,54,71,74]. DKK-1 gene polymorphisms may alter expression, activity, or association with bone disfigurement. Biomarker performance may vary across ethnicities or genetically distinct populations[43,46].

IMAGING CORRELATIONS AND DKK-1

Power Doppler ultrasound

Power Doppler ultrasound (PDUS) detects active synovial inflammation through neo-angiogenesis. It is related to systemic inflammation through erythrocyte sedimentation rate levels (r = 0.31, P = 0.01), CRP levels (r = 0.45, P < 0.01), and to clinical disease activity through DAS-28 score (r = 0.30, P = 0.01)[42,75,76]. PDUS is also related to DKK-1, ultrasound erosion count, and ultrasound erosion rate. This further strengthens its relationship with molecular indices[77]. It is also related to synovial histology, as it correlates with CD3+ T-cell (r = 0.54) and CD20+ B-cell (r = 0.54) infiltration.

From a prognostic standpoint, PDUS can detect early stages of disease, even at clinically silent metacarpophalangeal joints. PDUS can also predict disease relapse during dose reduction or therapy discontinuation, and it dynamically tracks treatment response[72,78]. The pauci-immune histopathological pathotype is the most resistant to current treatments, and its identification by synovial biopsy combined with PDUS may be critical for therapeutic decision-making[75,79].

Synovial thickening ultrasound

Synovial thickening ultrasound is a measure of synovial hypertrophy and is analogous to the chronic nature of the disease rather than active inflammation. Compared with inflammatory markers, synovial thickening ultrasound is similar only to CRP (r = 0.33, P = 0.01)[75,78,80,81].

Conventional radiography

Radiographic assessment of RA uses digital antero-posterior views of hands and feet scored with the SHS or the SENS to quantify joint erosion (JE) and JSN[8,49,82]. DKK-1 correlates with radiographic severity as measured by SENS. Baseline rheumatoid factor is more related to 12-month JE score (r = 0.46, P < 0.01) and erosion progression (r = 0.43, P < 0.01)[82]. In practice, DKK-1 may not predict radiographic progression if the patient is undergoing active treatment[83].

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is the most sensitive imaging technique for eRA detection. The findings, such as synovitis, bone marrow edema (BME), and early erosions, are visible on MRI before conventional radiographs[84-88]. BME is the best predictor of future radiographic progression, as it can show active osteitis and risks of structural damage. In early polyarthritis, MRI can detect synovitis in carpal joints and flexor tendon sheaths, which is the most reliable predictor of progression to classifiable RA[84,86,89]. Conversely, the absence of MRI synovitis has a high negative predictive value, assisting clinicians in excluding RA and avoiding unnecessary initiation of disease-modifying therapies[86,87]. The comparative roles of ultrasound, radiography, MRI, and DKK-1 across key clinical domains are presented in Table 2.

Table 2 Comparative roles of imaging modalities and dickkopf-1 in rheumatoid arthritis.

Parameter	Ultrasound	Radiography	MRI	DKK-1
Detects early synovitis	Yes (PDUS best)	No	Yes	Indirectly
Detects bone marrow edema	No	No	Yes (strongest predictor)	No
Sensitivity in eRA	High	Low	Very high	Moderate-high
Predicts future damage	Yes (persistent PDUS)	Yes (if baseline erosions)	Yes (BME)	Yes (erosions, JSN)
Remission assessment	Subclinical synovitis	No role	Confirms deep remission	Ongoing bone injury risk
Correlation with DKK-1	PDUS: ESR, CRP, DKK-1	RF, ACPA, DKK-1	BME: Erosive risk markers	N/A
Treatment monitoring	Excellent	Poor	Good (costly)	Good; falls with biologics
Key limitation	Operator dependent	Insensitive early disease	Cost and access	Assay variability

ACPA: Anti-citrullinated protein antibodies; BME: Bone marrow edema; CRP: C-reactive protein; DKK-1: Dickkopf-1; eRA: Early rheumatoid arthritis; ESR: Erythrocyte sedimentation rate; JSN: Joint space narrowing; MRI: Magnetic resonance imaging; N/A: Not applicable; PDUS: Power Doppler ultrasound; RF: Rheumatoid factor.

THERAPEUTIC RATIONALE FOR DKK-1 TARGETING

Preclinical evidence

DKK-1 blockade is currently being investigated in animal models of arthritis, including human TNF-transgenic mice, CIA, and glucose-6-phosphate isomerase-induced arthritis[90,91]. Anti-DKK-1 treatment in these models converted a bone-destructive phenotype into a bone-forming one. These data support DKK-1 as a molecular switch between bone destruction and repair[92].

Anti-DKK-1 treatment prevented inflammatory bone erosions even in the case of active inflammation, leading to reduced bone loss and inflammation[12,93]. Histological studies in these animal models showed increased osteoblast numbers, osteoid deposition, and osteophyte formation inside synovial joints following DKK-1 blockade. However, in the case of spinal and sacroiliac joint models, DKK-1 inhibition produced pathological joint fusion, demonstrating that excessive Wnt activation can produce ectopic ossification and ankylosis[93,94].

These preclinical trials highlight some mechanistic uncertainties despite their promising potential. They demonstrate that there is a possibility of pathologic bone formation, including ectopic ossification and joint fusion. Another concern relates to the biological effects of Wnt pathway modulation, as it is involved with several oncogenic pathways. The long-term risk of cancer development due to DKK-1 inhibition is uncertain. From the perspective of clinical development, DKK-1 has yet to enter phase-III clinical trials, and the existing studies have yet to establish efficacy in larger populations.

Indirect modulation by current therapies

TNF-α is an inducer of DKK-1 production in synovial fibroblasts. Inhibition of TNF-α synthesis with biologics such as etanercept, adalimumab, and infliximab lowers serum DKK-1 toward normal ranges, and changes in DKK-1 during treatment are known to affect disease progression[2,68]. IL-1 receptor antagonists (anakinra) and conventional disease-modifying antirheumatic drugs such as methotrexate are also known to reduce DKK-1 levels[68,70].

A contrasting observation is seen in psoriatic arthritis (PsA), where baseline DKK-1 levels may be lower than in healthy controls and can increase after anti-IL-17A treatment. Thus, DKK-1 has a disease-specific and pathway-specific behavior, demonstrating that DKK-1 cannot be generalized across spondyloarthropathies[16,95].

SAFETY CONSIDERATIONS AND LIMITATIONS FOR THERAPEUTIC DEVELOPMENT

DKK-1 blockade has ample risks despite its clear therapeutic effect. Animal models demonstrate that Wnt activation from DKK-1 inhibition can lead to pathological new bone formation (ectopic ossification) and joint fusion, especially in the axial skeleton[93]. In conditions where Wnt signaling is already heightened, such as PsA or axial spondyloarthritis, DKK-1 blockade could worsen ankylosis[70,96]. Wnt signaling interacts with oncogenic pathways, and the aspect of cancer risk is not known[97].

The reaction between DKK-1, sclerostin, and RANKL is not fully understood. It is not clear whether DKK-1 inhibition alone is sufficient or if blocking both DKK-1 and sclerostin would lead to better outcomes[98,99]. The therapeutic program has not entered clinical trials, and no phase III clinical trials of DKK-1 inhibitors in RA are reported. Careful dose-finding, imaging-based monitoring, and patient phenotyping will be essential components of any future trials.

GAPS IN CURRENT EVIDENCE

The use of DKK-1 levels as an RA biomarker faces several challenges that must be addressed before it reaches clinical use. Standardization of ELISA kits and measuring units is the first challenge. Serum and synovial fluid levels of DKK-1 constantly differ because of local TNF-α, which induces DKK-1 production in synovial fibroblasts, and the two compartments exhibit different clearance times[9,66,99].

On the imaging side, radiological assessment uses SENS for plain radiographs, OMERACT-defined scoring for ultrasound, and RAMRIS (RA MRI score) for MRI, and the absence of a unified scoring framework reduces cross-modality comparability when correlating with DKK-1 levels[8,12,49]. Biologically, the relationship among DKK-1, sclerostin, RSPO1, and RANKL remains incompletely mapped, and extra-articular effects of elevated or suppressed DKK-1 on trabecular bone and systemic osteoporosis require dedicated longitudinal investigation[98,99].

DKK-1 is a glycoprotein and endogenous soluble Wnt inhibitor that normally maintains bone homeostasis by reducing new bone growth. In RA, inflammatory cytokines disturb the balance and convert DKK-1 to a driver of joint injury. The bone remodeling patterns seen in degenerative osteoarthritis, characterized by pathological new bone formation, and RA, characterized by bone resorption, can be explained by the different behavior of DKK-1 in these two diseases[100]. Serum DKK-1 levels are higher in RA patients than in controls, with DAS-28 scores reaching r = 0.960 in some studies and CRP reaching r = 0.640[8,9,11,42,54]. The genetic difference is clear, where rs1896367 was associated with more frequent erosions in the feet, higher SHS, and greater JSN, collectively identifying a subgroup at high risk for aggressive structural damage[46,101,102].

The imaging data establishes a framework for clinical disease progression. PDUS indicates active inflammation along with DKK-1, which can predict future structural damage through persistent synovial signals. MRI provides the highest-sensitivity detection of BME, as it is the strongest predictor of radiographic disease progression. Conventional radiography is insensitive for early disease but serves as a prognostic indicator through baseline erosion quantification[42,75,76,84,86].

The preclinical evidence for DKK-1 blockade has demonstrated that erosion prevention that is independent of inflammation suppression can be achieved. The trials also offer the possibility of a bone-protective intervention that complements existing anti-inflammatory biologics[92,93,103]. The challenge lies in safely translating this new intervention, given the risks of ectopic ossification, the pathway's intersection with oncogenesis, and the absence of phase III trial data[9,43,97].

CONCLUSION

RA is a clinical spectrum of pathologies affecting the joints, ranging from mild self-limiting disease to severe disability. Intervention at the therapeutic window is essential to prevent structural damage. DKK-1 drives JE by suppressing Wnt signaling and causing an imbalance in bone homeostasis. Genetic variants lead to different levels of DKK-1 production, thus influencing circulating DKK-1 levels. Imaging modalities, such as PDUS and MRI BME, are markers of disease progression. Integration of histology, biomarkers, genetic loci, and imaging leads to better and safer standardization of the intervention. Standardization of ELISA kits and measuring units is the first challenge. DKK-1 inhibitors must address the risk of ectopic ossification, genetic variations and long-term safety monitoring. If these challenges are overcome in the future, then DKK-1 may evolve into both a biomarker and a therapeutic target.