Dickkopf-related Protein 1 Levels Research Articles

DKK-1 in psoriatic arthritis: Correlation with disease activity and enthesopathy

BackgroundPsoriatic arthritis (PsA) is a complex inflammatory disease with varied clinical characteristics. A pathognomonic characteristic of PsA is enthesitis. Entheseal inflammation ultimately leads to the production of new bone (enthesophytes). Dickkopf-related protein-1 (DKK-1) is a wingless (Wnt) inhibitor that inhibits osteoblast function. ObjectivesAssessment of the serum level of DKK-1 and its association with disease activity and enthesopathy in PsA patients. MethodsThis observational case–control study included 50 PsA patients and 50 healthy volunteers matched for age and gender. All participants were subjected to full medical history, clinical assessment, PSA activity using Disease Activity Index for Psoriatic Arthritis (DAPSA) score, the severity and extent of psoriasis were determined by the Psoriasis Area and Severity Index (PASI). Ultrasonographic assessment of the entheses was done in accordance with the Madrid Sonographic Enthesitis Index (MASEI). Serum level of DKK-1 and correlation with disease activity and enthesopathy in PsA patients were assessed. ResultsThere was no significant difference between patients and controls regarding age and sex. The mean value of SPARCC index, DAPSA score and PASI score were 6.74±4.58, 33.24±15.26, and 8.35±10.93, respectively. There was significant difference between patients and controls regarding the serum levels of DKK-1 and MASEI score (p<0.0001). There was a significant positive correlation between serum DKK-1 and MASEI (r: 0.43527, p: 0.00158), MASEI inflammatory (r: 0.37958, p: 0.00655), and MASEI damage (r: 0.38384, p: 0.00593). ConclusionsSerum DKK-1 levels were elevated in PsA patients and were found to be correlated with MASEI score for enthesopathy.

Dickkopf-Related Protein 1 (DKK-1) as a Possible Link between Bone Erosions and Increased Carotid Intima-Media Thickness in Psoriatic Arthritis: An Ultrasound Study.

Psoriatic arthritis (PsA) is a heterogenous systemic inflammatory disorder that affects peripheral joints and skin, but also causes inflammation at entheseal sites, digits (dactylitis) and the axial skeleton. Despite considerable advances, our understanding of the pathogenesis and management of PsA is hampered by its complex clinical expression. We enrolled patients who met the ClASsification for Psoriatic Arthritis (CASPAR) criteria for PsA (n = 17), and healthy controls (n = 13). The lipid profile, C-reactive protein (CRP) and Dickkopf-related protein 1 (DKK-1) circulating levels were measured for all subjects. For the patients with PsA, (1) the erosive character of the articular disease was assessed by a musculoskeletal ultrasound and (2) the cardiovascular risk was evaluated using the Systematic Coronary Risk Evaluation (SCORE) chart and the ultrasound measurement of the carotid intima-media thickness. A higher titer of serum DKK-1 was associated with the presence of erosions (p < 0.005) and the cIMT correlated with DKK-1 levels in patients with PsA (r = 0.6356, p = 0.0061). Additionally, we observed a positive correlation between increased cIMT and CRP (r = 0.5186, p = 0.0329). Our results suggest that DKK-1 could be used as an early biomarker for the erosive character of the articular disease and for the assessment of the cardiovascular risk in PsA patients.

DKK-1 in psoriatic arthritis: Correlation with disease activity and enthesopathy

BackgroundPsoriatic arthritis (PsA) is a complex inflammatory disease with varied clinical characteristics. A pathognomonic characteristic of PsA is enthesitis. Entheseal inflammation ultimately leads to the production of new bone (enthesophytes). Dickkopf-related protein-1 (DKK-1) is a wingless (Wnt) inhibitor that inhibits osteoblast function. ObjectivesAssessment of the serum level of DKK-1 and its association with disease activity and enthesopathy in PsA patients. MethodsThis observational case–control study included 50 PsA patients and 50 healthy volunteers matched for age and gender. All participants were subjected to full medical history, clinical assessment, PSA activity using Disease Activity Index for Psoriatic Arthritis (DAPSA) score, the severity and extent of psoriasis were determined by the Psoriasis Area and Severity Index (PASI). Ultrasonographic assessment of the entheses was done in accordance with the Madrid Sonographic Enthesitis Index (MASEI). Serum level of DKK-1 and correlation with disease activity and enthesopathy in PsA patients were assessed. ResultsThere was no significant difference between patients and controls regarding age and sex. The mean value of SPARCC index, DAPSA score and PASI score were 6.74±4.58, 33.24±15.26, and 8.35±10.93, respectively. There was significant difference between patients and controls regarding the serum levels of DKK-1 and MASEI score (p<0.0001). There was a significant positive correlation between serum DKK-1 and MASEI (r: 0.43527, p: 0.00158), MASEI inflammatory (r: 0.37958, p: 0.00655), and MASEI damage (r: 0.38384, p: 0.00593). ConclusionsSerum DKK-1 levels were elevated in PsA patients and were found to be correlated with MASEI score for enthesopathy.

Changes in Serum Bone Metabolism Markers after Living Donor Liver Transplantation (LDLT) and Their Association with Fracture Occurrences.

Living donor liver transplantation (LDLT) is lifesaving, but can lead to osteoporosis and fractures. In our 3-year study of 25 LDLT recipients, we observed significant reductions in lumbar spine and femoral neck T scores, along with bone resorption marker reductions and liver regeneration marker increases. Serum calcium levels increased, while osteoprotegerin (OPG) decreased and Dickkopf-related protein 1 (DKK-1) increased. Patients who suffered fractures within 3 years of LDLT had higher serum OPG, lower serum nuclear factor kappa B ligand (RANKL), a higher OPG/RANKL ratio and higher serum DKK-1 levels. OPG, RANKL, OPG/RANKL ratio and DKK-1 levels before LDLT predicted hip or spine fractures within three years after LDLT. Further research is necessary to determine the optimal level of osteoclastic activity for preventing fracture onset.

The Increasing Level of DKK-1 as a New Bone Formation Factor in Patients with Early Spondyloarthritis.

The role of dickkopf-related protein 1 (DKK-1) in radiographic development may become a robust marker for early spondyloarthritis (SpA) diagnosis. This study aimed at determining the serum DKK-1 profile in patients with SpA and investigating its relationship with SpA progression. Supported by analyzing the BMD data which aims to affirm the potential of DKK-1 as a biomarker for early diagnosis of SpA, this research may become the early study to produce a robust tool to diminish the fatal impacts in SpA. This cross-sectional study included patients with SpA using ASAS 2010 criteria from Dr. Soetomo General Hospital, Indonesia. Collected data included patients' general characteristics, disease duration, disease activity using ASDAS-CRP and ASDAS-ESR, serum DKK-1 levels, and BMD. The patients were classified as early SpA if the disease duration was ≤5 years and established SpA if the disease duration was >5 years, while the low BMD was indicated by Z score ≤ -2.00. The correlation was tested using the Spearman or Pearson test. The differences in patients' characteristics among early and established SpA and also between low and normal BMD were tested using the unpaired T-test or the Mann-Whitney test. The serum DKK-1 levels in early SpA (7365 ± 2067 pg/dL) were significantly higher than those in established SpA (5360 ± 1054 pg/dL). Serum DKK-1 levels were also associated with disease duration (r = -0.370, p = 0.040) and BMD at the total hip (r = 0.467, p = 0.028). The differences in all patients' clinical parameters were not found between patients with low BMD at any site and patients with normal BMD unless in the BMI (p = 0.019). Our findings found DKK-1 as a potential diagnostic marker for early SpA. Early diagnosis may lead to rapid treatment to delay disease progression and prevent future impairment.

Dickkopf-1 and ROCK2 upregulation and associated protein aggregation in pseudoexfoliation syndrome and glaucoma

AimsThe etiology of pseudoexfoliation (PEX), a stress-induced fibrillopathy and a leading cause of secondary glaucoma worldwide, remains limited. This study aims to understand the role of the Wnt antagonist Dickkopf-related protein 1 (DKK1) in PEX pathophysiology and assess its candidature as a biomarker for PEX. Main methodsExpression levels of DKK1 and Wnt signaling genes were assayed in the anterior ocular tissues of study subjects by qRT-PCR, Western blotting, and immunohistochemistry. Protein aggregation was studied through Proteostat staining. Role of DKK1 in protein aggregation and regulation of target Wnt signaling genes was elucidated through overexpression and knockdown studies in Human Lens Epithelial cells (HLEB3). Levels of DKK1 in circulating fluids were assayed through ELISA. Key findingsDKK1 upregulation was observed in lens capsule and conjunctiva tissues of PEX individuals compared to controls correlating with an upregulation of the Wnt signaling target, ROCK2. Proteostat staining showed increased protein aggregates in lens epithelial cells of PEX patients. HLE B-3 cells overexpressed with DKK1 showed increased protein aggregates along with upregulation of ROCK2, and knockdown of DKK1 in HLE B-3 cells demonstrated downregulation of ROCK2. Further, ROCK2 inhibition by Y-27632 in DKK1 overexpressed cells showed that DKK1 regulated protein aggregation via ROCK2. Also, increased levels of DKK1 were observed in patients' plasma and aqueous humor compared to controls. SignificanceThis study shows that DKK1 and ROCK2 might play a role in protein aggregation in PEX. Further, elevated levels of DKK1 in aqueous humor serve as a fair classifier of pseudoexfoliation glaucoma.

The Relationship between Dickkopf-Related Protein-1 (DKK-1) Plasma Levels and Impaired Cognitive Function in HIV Patients

Background: Dickkopf-related protein – 1 (DKK-1) is an antagonist protein to the Wingless (Wnt)-β catenin signal. Dysregulation of Wnt-β catenin signaling by DKK-1 causes disruption of neuronal synapses, which can result in impaired cognitive function. Impaired cognitive function in people with HIV or HIV-associated neurocognitive disorder (HAND) is a spectrum of cognitive disorders related to HIV neuroinvasion and neuroinflammation, which significantly results in impaired cognitive function and daily activity. This study aimed to assess the relationship between plasma DKK-1 levels and impaired cognitive function in HIV patients.&#x0D; Methods: This study used a cross-sectional design, consisting of 84 HIV sufferers who went to the voluntary counseling and testing (VCT) polyclinic at Dr. M. Djamil General Hospital, Padang, Indonesia, in the period December 2022 - March 2023, who met the inclusion and exclusion criteria. Cognitive function was assessed using the Montreal Cognitive Assessment Indonesian version (MoCa-Ina), and daily activity function using the instrumental activity of daily living (IADL) examination. Plasma DKK-1 levels were measured using the enzyme-linked immunosorbent assay (ELISA) method.&#x0D; Results: The mean plasma DKK-1 level of HIV sufferers was 358.4 (+ 157.6) pg/mL. ANI type disorder was found in 78.6%, MND in 21.4%, and no HAD type. There was a significant relationship between plasma DKK-1 levels and impaired cognitive function in HIV patients (OR = 2.82, CI95% = 1.128-7.043, p = 0.025), but there was no significant difference in plasma DKK-1 levels between types of cognitive impairment ANI and MND (p = 0.858).&#x0D; Conclusion: Plasma DKK-1 levels are significantly associated with impaired cognitive function in HIV patients.

PMON161 Decreased serum Wnt antagonist levels in patients with active acromegaly

Abstract Objectives The Wnt signalling pathway is an important modulator of bone metabolism. This study aims to clarify the changes in Wnt antagonists in active and biochemically controlled acromegalic patients. Methods We recruited 77 patients newly diagnosed with acromegaly. Of those, 41 patients with complete follow-up data were included. Thirty healthy patients matched for age, sex, and body mass index served as controls. Wnt antagonists [sclerostin (SOST), dickkopf-related protein 1 (DKK-1), and Wnt inhibitory factor 1 (WIF-1)], bone turnover markers [osteocalcin, procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX)] and the bone remodelling index were investigated at baseline and posttreatment. Results Acromegalic patients had higher serum osteocalcin, P1NP, and CTX and a higher bone remodelling index than controls (all P &amp;lt; 0.01). Serum SOST, DKK-1 and WIF-1 levels were significantly decreased in acromegalic patients compared to controls (all P &amp;lt; 0.01). Serum SOST and WIF-1 levels correlated negatively with growth hormone levels; SOST levels were positively correlated with WIF-1. Posttreatment, serum bone turnover markers and the bone remodelling index decreased, while SOST and WIF-1 significantly increased (P &amp;lt; 0.05). DKK-1 levels did not change compared to baseline (P &amp;gt; 0.05). In biochemically controlled patients, SOST, WIF-1 and bone turnover markers almost reached normal levels (all P &amp;gt; 0.05). Conclusion Patients with active acromegaly exhibited significantly decreased Wnt antagonist levels. The reduction in Wnt antagonists might be involved in the compensatory mechanism of increased bone fragility in active acromegaly. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Dickkopf-Related Protein 1 as Response Marker for Transarterial Chemoembolization of Hepatocellular Carcinomas.

Simple SummaryThe response of hepatocellular carcinomas (HCC) to transarterial chemoembolization (TACE) is variable. In view of the dynamic development of treatment options for HCCs, an early selection of the most effective therapy for maximizing individual treatment success has a high medical need. We show that serum levels of circulating Dickkopf-related protein 1 (DKK-1) are associated with a 12-week response to subsequent TACE in European patients. DKK-1 levels also allowed for identification of responders in patients with normal levels of alpha fetoprotein. Our findings are a step toward developing DKK-1 as a novel HCC response marker and an impulse to investigate the mechanisms underlying the treatment response of HCCs.Background and Aims: In the treatment of hepatocellular carcinoma (HCC), response prediction to transarterial chemoembolization (TACE) based on serum biomarkers is not established. We have studied the association of circulating Dickkopf-related protein 1 (DKK-1) with baseline characteristics and response to TACE in European HCC patients. Methods: Patients with HCC treated with TACE from 2010 to 2018 at a tertiary referral hospital were retrospectively enrolled. Levels of DKK-1 were measured in serum samples collected before TACE. Response was assessed according to mRECIST criteria at week 12 after TACE. Results: Ninety-seven patients were enrolled, including seventy-nine responders and eighteen refractory. Before TACE, median DKK-1 serum levels were 922 [range, 199–4514] pg/mL. DKK-1 levels were lower in patients with liver cirrhosis (p = 0.002) and showed a strong correlation with total radiologic tumor size (r = 0.593; p < 0.001) and with Barcelona Clinic Liver Cancer stages (p = 0.032). Median DKK-1 levels were significantly higher in refractory patients as compared to responders (1471 pg/mL [range, 546–2492 pg/mL] versus 837 pg/mL [range, 199–4515 pg/mL]; p < 0.001), and DKK-1 could better identify responders than AFP (AUC = 0.798 vs. AUC = 0.679; p < 0.001). A DKK-1 cutoff of ≤1150 pg/mL was defined to identify responders to TACE with a sensitivity of 78% and specificity of 77%. DKK-1 levels were suitable to determine response to TACE in patients with low AFP serum levels (AFP levels < 20 ng/mL; AUC = 0.843; 95% CI [0.721–0.965]; p = 0.003). Conclusion: DKK-1 levels in serum are strongly associated tumor size and with response to TACE in European HCC patients, including those patients with low AFP levels.

New Emerging Biomarkers for Bone Disease: Sclerostin and Dickkopf-1 (DKK1).

A healthy skeleton depends on a continuous renewal and maintenance of the bone tissue. The process of bone remodeling is highly controlled and consists of a fine-tuned balance between bone formation and bone resorption. Biochemical markers of bone turnover are already in use for monitoring diseases and treatment involving the skeletal system, but novel biomarkers reflecting specific biological processes in bone and interacting tissues may prove useful for diagnostic, prognostic, and monitoring purposes. The Wnt-signaling pathway is one of the most important pathways controlling bone metabolism and consequently the action of inhibitors of the pathway such as sclerostin and Dickkopf-related protein 1 (DKK1) have crucial roles in controlling bone formation and resorption. Thus, they might be potential markers for clinical use as they reflect a number of physiological and pathophysiological events in bone and in the cross-talk with other tissues in the human body. This review focuses on the clinical utility of measurements of circulating sclerostin and DKK1 levels based on preanalytical and analytical considerations and on evidence obtained from published clinical studies. While accumulating evidence points to clear associations with a number of disease states for the two markers, and thus, the potential for especially sclerostin as a biochemical marker that may be used clinically, the lack of standardization or harmonization of the assays still hampers the clinical utility of the markers.

Bone Marrow Adiposity, Bone Mineral Density and Wnt/β-catenin Pathway Inhibitors Levels in Hemodialysis Patients

BackgroundMarrow adipose tissue (MAT) is known to accumulate in patients with chronic kidney disease. This pilot study aimed to evaluate bone mineral density (BMD), MAT, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) using computed tomography (CT) scans and to explore correlations between bone parameters, circulating Wnt/β-catenin pathway inhibitor levels, and adipose tissue parameters.MethodsSingle-center cross-sectional pilot study conducted in hemodialysis patients at the Centre Universitaire de Québec, Hôtel-Dieu de Québec hospital, Canada. CT-scan slices were acquired at the levels of the hip, L3 vertebra, and tibia. Volumetric and areal BMD, tibia cortical thickness, VAT and SAT area, and fat marrow index (FMI) were analyzed using the Mindways QCT Pro software. Blood levels of sclerostin, dickkopf-related protein 1 (DKK1), fibroblast growth factor 23, and α-Klotho were assessed. Spearman’s rho test was used to evaluate correlations.ResultsFifteen hemodialysis patients (median age, 75 [66–82] years; 80% male; dialysis vintage, 39.3 [27.4–71.0] months) were included. While inverse correlations were obtained between L3 FMI and BMD, positive correlations were found between proximal tibial FMI and vertebral and tibial BMD, as well as with tibial (proximal and distal) cortical thickness. VAT had a positive correlation with α-Klotho levels, whereas L3 FMI had a negative correlation with DKK1 levels.ConclusionsCT-scan allows simultaneous evaluation of bone and marrow adiposity in dialysis patients. Correlations between MAT and BMD vary depending on the bone site evaluated. DKK1 and α-Klotho levels correlate with adipose tissue accumulation in dialysis patients.

MO947: Evaluation of Bone Metabolism Markers in Kidney Transplant Recipients

Abstract BACKGROUND AND AIMS Immunosuppressive therapies, pre-existing renal osteodystrophy, de novo hyperparathyroidism, and other traditional risk factors influence Mineral and Bone Disorder (MBD) after kidney transplantation. However, little is known about their effect on bone metabolism biomarkers. Therefore, we aimed to understand how kidney transplant affects bone metabolism markers in comparison to patients on hemodialysis and healthy individuals. METHOD This is a cross-sectional study with 57 kidney transplant patients, 36 patients on hemodialysis, and 31 healthy controls. Plasma concentrations of Dickkopf-related protein 1 (DKK1), osteoprotegerin (OPG), osteocalcin (OC), osteopontin (OPN), sclerostin (SOST) and fibroblast growth factor 23 (FGF-23) were measured using the Luminex-based microbead assay (HBNMAG-51K, Millipore, Billerica, MA) in these three groups. Associations between the measurements of these molecules with clinical, demographic, and laboratory data were evaluated. For variables without Gaussian distribution, Mann–Whitney test was used to compare two groups and the Kruskal–Wallis test for comparisons between more than two groups. For variables with normal distribution, comparisons between two groups were made by unpaired Student's t-test and for more than two groups by analysis of variance followed by Bartlett’s post-test. Pearson or Spearman tests were adopted to evaluate correlations according to the variables’ distribution. All statistical tests were two-tailed with a significance level of P &amp;lt; 0.05. RESULTS Transplant recipients had significantly lower levels of DKK1 (P &amp;lt; 0.001), OPG (P &amp;lt; 0.001), OC (P &amp;lt; 0.001), OPN (P = 0.001), OST (P &amp;lt; 0.001) and FGF-23 (P &amp;lt; 0.001) when compared with patients on hemodialysis. In comparison to healthy controls, transplant recipients also presented lower levels of DKK1 (P = 0.019), OPG (P &amp;lt; 0.001), OC (P = 0.027), SOST (P &amp;lt; 0.001) and FGF-23 (P = 0.043) (Figure 1). Regarding demographic data, women presented lower plasma SOST levels when compared with men in the hemodialysis group (P = 0.012). Different correlations between the human bone metabolism components were detected in transplant recipients and hemodialysis patients. In the transplant group, DKK1 was positively correlated with SOST (r = 0.484, P = 0.001), OPN (r = 0.420, P = 0.005) and OPG (r = 0.521, P &amp;lt; 0.001). In the same group, SOST levels were positively correlated with FGF-23 (r = 0.424, P = 0.027, Figure 2D) and OPG (r = 0.703, P &amp;lt; 0.001), while OC only positively correlated with OPN (r = 0.572, P &amp;lt; 0.001). By contrast, patients on hemodialysis only showed positive correlations between OPN and DKK1 (r = 0.420, P = 0.005) and between SOST and OPG (r = 0.757, P &amp;lt; 0.001). Concerning laboratory parameters and their correlations with human bone metabolism molecules, both transplant recipients and hemodialysis patients showed a negative correlation between 25(OH)vitamin D levels and FGF-23. On the other hand, ALP levels were positively correlated with different molecules in the two groups. In transplant patients, ALP levels positively correlated with OPN (r = 0.572, P &amp;lt; 0.001), while, in hemodialysis patients, the positive correlation was with OPG (r = 0.548, P = 0.012). CONCLUSION Our findings showed a reduction in bone metabolism markers, DKK1, OPG, OC, OPN and SOST after kidney transplantation. The first years after kidney transplantation modulate MBD markers, revealing a significant improvement of MBD associated with end-stage kidney disease.

High Serum Levels of Wnt Signaling Antagonist Dickkopf-Related Protein 1 Are Associated with Impaired Overall Survival and Recurrence in Esophageal Cancer Patients.

Dickkopf-related protein 1 (DKK1), an antagonist of the canonical Wnt pathway, has received tremendous attention over the past years as its dysregulation is said to be critically involved in a wide variety of gastrointestinal cancers. However, the potential clinical implications of DKK1 remain poorly understood. Although multimodal treatment options have been implemented over the past years, esophageal cancer (EC) patients still suffer from poor five-year overall survival rates ranging from 15% to 25%. Especially prognostic factors and biomarkers for risk stratification are lacking to choose the most beneficial treatment out of the emerging landscape of different treatment options. In this study, we analyzed the serum DKK1 (S-DKK1) levels of 91 EC patients prior to surgery in a single center study at the University Medical Center Hamburg-Eppendorf by enzyme-linked immunosorbent assay. High levels of S-DKK1 could be especially observed in patients suffering from esophageal adenocarcinoma which may promote the hypothesis of a crucial role of DKK1 in inflammation. S-DKK1 levels of ≥5800 pg/mL were shown to be associated with unfavorable five-year survival rates and the presence of CTCs. Interestingly, significantly lower S-DKK1 levels were detected in patients after neoadjuvant treatment, implying that S-DKK1 may serve as a useful biomarker for treatment monitoring. Multivariate analysis identified S-DKK1 as an independent prognostic marker with respect to overall survival in EC patients with a hazard ratio of 2.23. In conclusion, our data implicate a negative prognostic role of DKK1 with respect to the clinical outcome in EC patients. Further prospective studies should be conducted to implement S-DKK1 into the clinical routine for risk stratification and treatment monitoring.

Serum biomarkers for bisphosphonate-related osteonecrosis of the jaw: a prospective clinical study.

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is an adverse effect of long-term bisphosphonate therapy. This study aimed to identify bone biomarkers for ONJ risk assessment and diagnosis. This prospective study included patients with histories of bisphosphonate therapy without current ONJ who were in need of dentoalveolar surgery of the jaw area. Serum levels of 12 possible bone markers, selected based on their involvement in ONJ pathogenesis, were compared between ONJ and control groups before dentoalveolar surgery (T0), at 8 postoperative weeks (T1), and at 4months after diagnosis(T2). Seventy-six patients who met the inclusion criteria were included in the study; 33 were assigned to the ONJ group, and 43 patients without ONJ signs or symptoms after dentoalveolar surgery were assigned to the control group. In the ONJ group, at both T0 and T1, the mean tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) levels were significantly lower and the mean Dickkopf-related protein 1 (DKK1) levels were significantly higher than the corresponding values for the control group. Linear mixed model analysis revealed significant group effects over time for serum TRACP 5b and DKK1 after adjusting for demographic, pharmacological, and diagnostic variables. Lower serum levels of TRACP 5b under a specified cut-off value (≤ 2.899 U/L) at T0 indicated a 20.40-fold increased risk of ONJ development. Patients with abnormally low serum levels of TRACP 5b and high serum levels of DKK1 should be monitored closely before and after dentoalveolar surgery for the prevention and early diagnosis of ONJ.

Serum midkine is a more sensitive predictor for hepatocellular carcinoma than Dickkopf-1 and alpha-L-fucosidase in cirrhotic HCV patients.

Alpha fetoprotein (AFP) level is the gold standard diagnostic tool for detection and monitoring hepatocellular carcinoma (HCC) but with low sensitivity. Thus, the identification of alternative or combined serum markers of HCC is highly needed. Therefore, the aim of this work was to verify the value of serum midkine (MDK), Dickkopf-related protein 1 (DKK1), and alpha-L-fucosidase (AFU) in detection of HCC.We recruited 244 subjects to the present study; 89 with liver cirrhosis, 86 cirrhotic hepatitis C virus (HCV) induced HCC, and 69 apparently healthy volunteers as controls. Serum AFP, MDK, DKK1, and AFU were measured by ELISA.Patients with HCC showed significantly higher serum MDK, DKK1, and AFU levels compared with those patients with liver cirrhosis and healthy controls (X2 = 179.56, 153.94, and 90.07 respectively) (P < .001 in all). In HCC cases, neither of MDK, DKK1, or AFU was correlated with tumor number. On the other hand, only serum DKK1 was significantly higher in lesions >5 cm, those with portal vein thrombosis and advanced HCC stage. Receiver operator characteristic (ROC) curve analysis showed that serum MDK levels discriminated between cirrhosis and HCC at a sensitivity of 100%, a specificity of 90% at cut-off value of >5.1 ng/mL.Although our results showed that serum MDK, DKK-1, and AFU are increased in HCC cases only MDK may be considered as the most promising serological marker for the prediction of the development of HCC in cirrhotic HCV patients.

Relation of the Serum Levels of DKK-1 and Osteoprotegerin with Bone Mass in Tightly Controlled Rheumatoid Arthritis.

To analyze the association between serum levels of osteoprotegerin (OPG) and Dickkopf-related protein 1 (DKK-1) and the annual percent change (Δ%) in bone mineral density (BMD) in patients with tightly controlled rheumatoid arthritis (RA). Observational mixed-study. RA patients followed-up with a tight-control strategy were included. Bone densitometries were performed at baseline (T0) and follow-up (T1) and serum levels of OPG and DKK-1 were measured by ELISA also in T0 and T1; additional clinical variables included disease activity measures, and treatment for RA and osteoporosis. Descriptive bivariate and multivariate analyses, stratified by gender, were performed. We included 97 RA patients (70% female, with a mean age of 53 years, and 76% with low activity by DAS28); 95% were treated with DMARDs and 37% with anti-osteoporotic drugs. Mean time between T0 and T1 was 2.7 years. Most patients had their BMD improved. The mean Δ%BMD was +0.42% for lumbar spine, +0.15% for femoral neck and +0.91% for total femur. In men, baseline OPG was significantly associated with higher BMD loss (β coefficient -0.64) at the femoral neck. In women, DKK-1 was associated with higher BMD loss at the femoral neck (β coefficient -0.09), and total femur (β coefficient -0.11); however, DKK-1 was associated with lower BMD loss at the lumbar spine (β coefficient 0.06). In tightly controlled RA patients, we have found no evidence of bone loss. The role of DKK1 and OPG seems small and might be related to sex and location.

Serum Dickkopf-1 in Combined with CA 19-9 as a Biomarker of Intrahepatic Cholangiocarcinoma.

Simple SummaryCholangiocarcinoma (CCC) is a rare cancer, but its incidence and mortality have been increased in the past few decades worldwide, representing a global health problem. CCC is usually asymptomatic in early stages and, therefore, often diagnosed when the disease is already in advanced stages, which highly compromises therapeutic options, resulting in a dismal prognosis. The current diagnosis of CCC by non-invasive approaches such as serum biomarker, carbohydrate antigen 19-9 (CA 19-9), is not accurate enough due to the limitations in its low sensitivity, especially at the early stages of the disease. Therefore, new biomarkers with higher sensitivity and specificity are needed. As the clinical significance of dickkopf-related protein-1 (DKK-1) has been reported in various tumors including intrahepatic CCC (ICC), we aimed to identify the diagnostic and prognostic performance of the DKK-1 and its additive effect combined with CA 19-9 in patients with CCC.Dickkopf-related protein 1 (DKK-1) has a diagnostic and prognostic value in various malignant tumors. We investigated the diagnostic and prognostic performance of DKK-1 in combination with carbohydrate antigen 19-9 (CA 19-9) in cholangiocarcinoma (CCC) patients. Serum DKK-1 levels were measured using enzyme-linked immunosorbent assay. The receiver operating characteristic (ROC) curve, area under ROC (AUROC) analyses, Kaplan–Meier method, and Cox proportional hazard model were used to evaluate the diagnostic and prognostic performance of DKK-1 in combination with CA 19-9. We checked DKK-1 levels in 356 CCC patients and found that DKK-1 was significantly elevated only in 79 intrahepatic CCC (ICC) patients compared to controls (340.5 vs. 249.8 pg/mL, p = 0.002). The optimal cutoff level of DKK-1 used to identify ICC patients was 258.0 pg/mL (AUROC = 0.637, sensitivity = 59.5%, specificity = 56.9%, positive predictive value (PPV) = 40.5%, negative predictive value (NPV) = 74.0%, positive likelihood ratio (LR) = 1.38, and negative LR = 0.71). Using this cutoff, 47 (59.5%) patients were correctly diagnosed with ICC. DKK-1 in combination with CA 19-9 showed a better diagnostic performance (AUROC = 0.793, sensitivity = 74.7%, specificity = 56.3%, PPV = 45.7, NPV = 81.8, positive LR = 1.71, and negative LR = 0.45) than CA 19-9 alone. The low DKK-1 and CA 19-9 expression group had a significantly longer overall survival (OS) than the high expression group (p = 0.006). The higher level of DKK-1 and CA 19-9 was independently associated with shorter OS (hazard ratio = 3.077, 95% confidence interval 1.389–6.819, p = 0.006). The diagnostic and prognostic performance of DKK-1 in combination with CA 19-9 might be better than those of CA 19-9 alone in ICC patients.

Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels

Background: The Wnt/β-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). Methods: GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D₃ and 1,25-dihydroxyvitamin D₃. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. Results: The median [IQR] age was 64 years [53.0–71.0], and the median [IQR] mGFR was 32.6 [21.7–60.6] mL/min. DKK1 decreased (r = 0.6, p < 0.001) and sclerostin increased (r = −0.4, p < 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D₃ in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. Conclusion: The results of this study demonstrate opposing trends in Wnt/β-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

Association of Dickkopf-1 Polymorphisms With Radiological Damage and Periodontal Disease in Patients With Early Rheumatoid Arthritis: A Cross-Sectional Study.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that increased bone resorption. Periodontal disease (PD) is an associated risk factor of RA. Studies suggest an association between bone markers such as the dickkopf-related protein 1 (DKK-1) and progression of radiological damage. We aimed to evaluate the marker DKK-1, its polymorphisms in patients with early rheumatoid arthritis (eRA), and its association with rheumatic, radiological, and periodontal variables. This is a cross-sectional study. Samples were obtained from 63 patients with eRA. Radiographs of hands and feet were evaluated by Sharp-van der Heijde score (SHS) and Simple Erosion Narrowing Score (SENS). Serum DKK-1 levels and high-resolution fusion analysis was used for polymorphisms (rs1896368, rs1896367, rs1528873). Bivariate analyses were performed. Individuals heterozygous for rs1896367 had more frequent erosions (p = 0.026) and joint space narrowing (p = 0.005) in the feet, higher SHS (p = 0.016), and higher SENS (p ≤ 0.001). Patients homozygous for rs1896368 had less frequent joint space narrowing in hands and feet as assessed by SHS and less presence of erosions by SENS (odds ratio, 0.04; 95% confidence interval, 0.00-0.93; p < 0.05). The presence of PD was associated with the homozygous of rs1896367 (p = 0.009) and the heterozygous of rs1896368 (p = 0.033). Polymorphism rs1896367 seems to be associated with greater radiological compromise; rs1896368 confers protection against bone damage in Colombian eRA patients.

Clinical significance and prognostic value of tumor necrosis factor-α and dickkopf related protein-1 in ankylosing spondylitis.

Ankylosing spondylitis (AS) frequently occurs in people aged 30-45 years, and its prevalence is generally believed to be between 0.1% and 1.4% globally. At present, the "gold standard" for diagnosis of AS requires the provision of pelvic X-rays, which makes it more difficult to perform in population-based epidemiological studies. Therefore, the identification of serological indicators related to the diagnosis, treatment, and prognosis of AS patients is of great significance. To analyze the therapeutic, diagnostic significance and prognostic value of dickkopf-related protein-1 (DKK-1) and tumor necrosis factor-α (TNF-α) in AS. A total of 113 patients with active AS were selected as the research group, and 100 healthy subjects who underwent physical examination were selected as the control group. The levels of DKK-1 and TNF-α in peripheral blood in the two groups were compared. The diagnostic and predictive values of DKK-1 and TNF-α for AS were analyzed with ROC curves, and the factors influencing AS recurrence were analyzed with COX regression. Before treatment, the research group showed lower DKK-1 levels but higher TNF-α levels than the control group (both a P < 0.05). In the research group, DKK-1 was up-regulated and TNF-α was down-regulated after 12 wk of treatment (a P < 0.05). The area under the curve, sensitivity and specificity of DKK-1 combined with TNF-α for diagnosing AS were 0.934, 82.30% and 97.00%, respectively. Before treatment, the area under the curve, cutoff value, sensitivity and specificity of DKK-1 for predicting the curative effect were 0.825, 68.42 pg/mL, 73.68% and 80.00%, respectively, and those of TNF-α were 0.863, 32.79 ng/L, 92.11% and 77.33%, respectively. DKK-1 and TNF-α levels after treatment were closely related to the curative effect (a P < 0.05). C-reactive protein, the Bath Ankylosing Spondylitis Disease Activity Index, DKK-1, and TNF-α were risk factors for AS recurrence (a P < 0.05). DKK-1 and TNF-α are effective in the diagnosis and treatment of AS and are risk factors for its recurrence. In addition, DKK-1 may be a potential target for the diagnosis of AS.