Serum Levels Of Dickkopf-1 Research Articles

Associations of serum Dickkopf-1 levels with disease severity and 90-day Prognosis after spontaneous intracerebral hemorrhage: results from the prospective cohort study.

Dickkopf-1 (DKK-1) may be involved in inflammatory response and secondary brain injury after acute brain injury. We gauged serum DKK-1 levels and further assessed its correlation with disease severity and investigated its predictive value for 90-day prognosis in patients with spontaneous intracerebral hemorrhage (sICH). Serum DKK-1 levels were measured in 128 sICH patients and 128 healthy controls. The severity of sICH was assessed using the Glasgow Coma Scale (GCS) scores and hematoma volumes. Poor prognosis was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at 90days after stroke. Multivariate analysis was performed to identify associations of serum DKK-1 levels with disease severity, early neurological deterioration (END) and poor prognosis. Receiver operating characteristic curve (ROC) was built to investigate the prognostic predictive capability. The serum DKK-1 levels of patients were significantly higher than those of controls (median, 4.74ng/mL versus 1.98ng/mL; P < 0.001), and were independently correlated with hematoma volumes (ρ = 0.567, P < 0.001; t = 3.444, P = 0.001) and GCS score (ρ = -0.612, P < 0.001; t = -2.048, P = 0.043). Serum DKK-1 significantly differentiated patients at risk of END (area under ROC curve (AUC), 0.850; 95% confidence interval (CI), 0.777-0.907; P < 0.001) and poor prognosis (AUC, 0.830; 95% CI, 0.753-0.890; P < 0.001), which had similar prognostic ability, as compared to GCS scores and hematoma volumes. Subsequent Logistic regression model affirmed that GCS score, hematoma volume, and serum DKK-1 levels were independently associated with END and poor prognosis at 90days after sICH. The models, which contained them, performed well using ROC curve analysis and calibration curve analysis. Serum DKK-1 levels are markedly associated with disease severity, END and 90-day poor prognosis in sICH. Hence, serum DKK-1 is presumed to be used as a potential prognostic biomarker of sICH.

The Role of Serum Dickkopf1 and CKAP4 Levels in Diagnosing Colorectal Cancer and Measuring the Disease Severity: A Prospective Study.

Background and Objective: Colorectal cancer (CRC) is among the most common types of cancer. Although the disease is treatable in its early stages, five-year survival falls below 20% in the later stages. CEA and CA19-9 are tumor markers used in the diagnosis and follow-up of the disease in clinical practice; however, their diagnostic effectiveness is insufficient. Therefore, the identification of biomarkers that can be easily studied from serum and can diagnose CRC and determine its severity is highly important. In this context, dickkopf1 (DKK1) and cytoskeleton-associated protein 4 (CKAP4) are both promising biomarkers. Materials and Methods: Serum DKK1 and CKAP4 levels were measured in 55 patients with CRC and 40 healthy controls. The patients with CRC were divided into groups based on pathological stages and histological differentiation. The serum levels of both proteins in patients with CRC were measured preoperatively and 10 and 30 days postoperatively. Results: Serum DKK1 and CKAP4 were significantly higher in the CRC group than in the healthy controls (p < 0.05). Serum levels of both proteins rose in line with the disease stage and grade but decreased following surgical resection. A positive correlation was observed between tumor diameter and protein blood levels. The diagnostic efficacy of DKK1 and CKAP4 in CRC (approximately 95%) was higher than that of markers such as CEA and CA19-9. Conclusions: The DKK1 and CKAP4 serum values of patients with CRC are promising biomarkers. They can potentially be used in CRC management, namely, in the diagnosis and treatment of tumor response access and in tumor aggressiveness prediction.

Abstract 3925: Cancer-associated fibroblast-derived Dickkopf-1 impairs anti-tumor immunity in breast cancer by suppressing NK cell-mediated cytotoxicity

Abstract Despite early diagnosis, 10-20% of breast cancer patients experience metastatic disease within 5-10 years. While it is established that breast cancer cells have the capacity to evade immune responses, the mechanisms driving this evasion remain elusive. Therefore, finding ways to enhance anti-tumor immunity is crucial to improve patient outcomes. Dickkopf-1 (DKK1) is a Wnt inhibitor whose levels correlate with poor prognosis and decreased immune infiltration in various cancers. In this study, we used mice orthotopically injected with the PyMT, EO771, and 4T1 breast cancer lines. In all models, we found elevated DKK1 serum levels, and its neutralization with an αDKK1 Ab resulted in a significant reduction in primary tumor growth but also in metastatic dissemination. To identify the source of DKK1, we examined its expression in the tumor. DKK1 was detected in stromal cells with a fibroblast-like morphology but not in cancer cells or immune infiltrates. Co-staining confirmed colocalization between DKK1 and the CAF marker αSMA. To address the role of CAF-derived DKK1, we specifically deleted DKK1 in CAFs by generating FSP1CreDkk1fl/fl and αSMACreERT2Dkk1fl/fl mice. Both models showed a significant reduction in primary tumor growth while maintaining comparable serum DKK1 levels, indicating locally produced DKK1 supports tumor growth. To understand how DKK1 promotes tumor progression, we conducted bulk RNAseq of tumor cells isolated from IgG or αDKK1 treated mice. While no changes related to cell viability or cell cycle were observed, immune response-related genes were upregulated in αDKK1-treated cells. In support of this, αDKK1 did not reduce tumor growth in NSG immune-compromised mice. To pinpoint the immune cell targeted by DKK1, we depleted T, NK cells, or macrophages in WT tumor-bearing mice treated with αDKK1. Remarkably, only NK cell depletion negated αDKK1 anti-tumor effects. In vitro assays further demonstrated that rDKK1 or the presence of CAFs reduced NK cell cytotoxicity against tumor cells while αDKK1 restored it. To assess whether DKK1 levels correlated with tumor progression and immune suppression in breast cancer patients, we analyzed DKK1 serum levels and circulating NK cells at the diagnosis of metastatic bone disease and 15-18 months after standard care. DKK1 levels were significantly elevated in patients with progressive bone disease compared to those with stable disease. Importantly, NK cells from the progressive disease cohort had reduced perforin and granzyme B expression at the follow-up visit compared to baseline, indicating reduced cytotoxicity. Furthermore, rDKK1 reduced perforin in NK cells from healthy donors. In sum, our data show DKK1 is an important regulator of breast cancer progression, and we report for the first time DKK1 directly impairs NK cell cytotoxicity, creating an immune suppressive environment resistant to treatment. Citation Format: Seunghyun Lee, Biancamaria Ricci, Roberta Faccio. Cancer-associated fibroblast-derived Dickkopf-1 impairs anti-tumor immunity in breast cancer by suppressing NK cell-mediated cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3925.

The predictive value of serum Dickkopf-1, Dickkopf-3 level to coronary artery disease and acute coronary syndrome

BackgroundPrevious studies have already confirmed the association between Dickkopf (Dkk) protein and the occurrence and progression of atherosclerosis. However, there is limited clinical evidence regarding the serum levels of Dickkopf-1 (Dkk1) and Dickkopf-3 (Dkk3) in relation to atherosclerotic cardiovascular disease (ASCVD), particularly acute coronary syndrome (ACS). Materials and methodsA total of 88 healthy volunteers and 280 patients with coronary artery disease (CAD) undergoing coronary angiography for angina between October 2021 and October 2022, including 96 cases of stable angina (SA), 96 of unstable angina (UA) and 88 of acute myocardial infarction (AMI) were included finally. The serum concentrations of Dkk1 and Dkk3 were measured using electrochemiluminescence of Meso Scale Discovery. The predictive value of single or combined application of serum Dkk1 and Dkk3 in CAD and ACS were evaluated. ResultsThe serum levels of Dkk1 were significantly higher in the SA group, UA group, and AMI group compared to the control group. Multivariable logistic regression analysis demonstrated that elevated serum Dkk1 levels were independent predictive factors for increased risk of CAD and ACS (OR = 1.027, 95%CI = 1.019–1.034, p < 0.001; OR = 1.045, 95%CI = 1.028–1.053, p < 0.001, respectively). Receiver operating characteristic curve (ROC) analysis showed that the optimal cutoff value of serum Dkk1 for predicting ACS was 205 ng/dl, with a sensitivity of 82.6% and specificity of 96.6%. The area under the curve (AUC) was 0.930 (95%CI: 0.899–0.961, p < 0.001). Regarding Dkk3, serum Dkk3 levels were elevated in CAD patients compared to the healthy control group, and significantly higher in ACS patients compared to SA patients. Serum Dkk3 was significantly associated with increased risk of CAD and ACS (OR = 1.131, 95%CI = 1.091–1.173, p < 0.001; OR = 1.201, 95%CI = 1.134–1.271, p < 0.001, respectively). ROC curve analysis showed that the optimal cutoff value of serum Dkk3 for predicting ACS was 50.82 ng/ml, with a sensitivity of 85.9% and specificity of 87.5%. The AUC was 0.925 (95%CI: 0.894–0.956, p < 0.001). When serum Dkk1 and Dkk3 are combined as predictive factors for ACS, the AUC was 0.975. ConclusionSerum levels of Dkk1 and Dkk3 are significantly associated with an increased risk of CAD and ACS, and they possess predictive value for CAD and ACS. The combination of serum Dkk1 and Dkk3 is a superior predictive factor for CAD and ACS.

Biomarkers of disability worsening in inactive primary progressive multiple sclerosis

ObjectiveTo investigate serum biomarkers of progression in inactive primary progressive multiple sclerosis (PPMS). MethodsWe measured protein biomarkers (growth differentiation factor-15 (GDF-15), dickkopf-1 (DKK-1), neuron specific enolase (NSE) and cathepsin-D) in serum samples from 39 patients with inactive PPMS included in a clinical trial enrolling people with PPMS (clinicaltrials.gov identifier NCT02913157) and investigated the association of these biomarker levels with clinical disability at baseline and during follow-up. We then performed a meta-analysis of publicly available transcriptomic datasets to investigate the gene expression of these biomarkers in the CNS in progressive MS. ResultsWhen compared with healthy controls, people with PPMS had higher serum levels of GDF-15, DKK-1 and cathepsin-D at baseline. These findings match those in our meta-analysis which found increased expression of GDF-15 and cathepsin-D in the CNS in progressive MS. At baseline, elevated serum DKK-1 was associated with worse Expanded Disability Status Scale (EDSS) and nine-hole peg test (9HPT) scores. None of the other biomarkers levels significantly correlated with EDSS, Timed 25-Foot Walk Test (T25FWT), 9HPT, or cognitive measures. However, serum GDF-15 and cathepsin-D were higher at baseline in participants who developed worsening disability. Our receiver operating characteristic curve showed that higher serum GDF-15 and cathepsin-D at baseline significantly discriminated between participants who worsened in T25FWT and 9HPT and those who remained stable. ConclusionsPatients with PPMS have altered levels of GDF-15, DKK-1 and cathepsin-D in serum, and GDF-15 and cathepsin-D may have predictive value in progression free of inflammatory activity in PPMS.

The clinical significance and diagnostic value of serum Dickkopf1 and CKAP4 levels in patients with gastric cancer: a prospective study.

Gastric cancer is diagnosed at an advanced stage in most patients, and the prognosis is poor. Novel biochemical markers of high diagnostic value for the detection of the disease are therefore important. Dickkopf1 (DKK1) and cytoskeleton-associated protein 4 (CKAP4) have been extensively studied as biomarkers in cancer patients. Serum DKK1 and CKAP4 levels in 58 patients with gastric cancer and 41 healthy controls were examined using an ELISA kit in this prospective study. The patients were subdivided into groups based on pathological TNM staging and histological grades. Serum levels of both proteins in the patients with gastric cancer were measured preoperatively, 10 and 30 days after surgery. Serum DKK1 and CKAP4 levels were significantly higher in the gastric cancer group compared to the healthy controls (p<0.05). Serum levels of both proteins increased in line with the pathological stage and histological grade of the gastric cancer. Serum CKAP4 and DKK1 levels decreased after surgical resection. Both serum levels also decreased significantly on day 30 after surgery compared to day 10 (p<0.05). Serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) positivity rates were below 20% in the gastric cancer group, while the diagnostic value (sensitivity and specificity) of serum CKAP-4 and DKK1 exceeded 80%. DKK1 and CKAP4 are biomarkers of high diagnostic value that can be used to diagnose and predict the severity of gastric cancer. These proteins can also be employed for disease monitoring after surgical resection. The diagnostic value of these proteins is higher than that of biomarkers such as CEA and CA19-9, which are routinely used in clinical practice.

E24 Does juvenile onset impact the serum levels of bone-forming biomarkers in adult patients with Spondyloarthritis?

Abstract Introduction The Wnt signalling pathway regulates bone metabolism. Dickkopf1 (DKK-1) and Sclerostin are potent inhibitors of this pathway, and their dysfunction would be responsible for bone formation phenomena in patients with spondyloarthritis (SpA). Osteoprotegerin (OPG), a potent inhibitor of osteoclasts, regulated by the Wnt pathway, has also been implicated in this bone ossification phenomenon. We aimed to assess the impact of juvenile-onset on the serum levels of DKK-1, sclerostin, and OPG in adult with spondyloarthritis. Methods It was a cross-sectional case control study including patients with SpA (meeting ASAS criteria). Data collected included sociodemographic and disease characteristics. Biomarker assays were performed using an ELISA technique. Results Among one hundred and nine included patients, seven patients had a juvenile onset of the disease (six males, one female). The mean age of disease onset was 12.8 ± 4.3 [5–16] years. The mean duration of SpA at inclusion was 15 ± 6 years [4 – 21]. Two (28.6%) patients had an axial form, and five (71.4%) had an axial and peripheral form. Three patients (42.9%) had entheseal involvement. The means of serum levels of DKK-1 and sclerostin in patients with juvenile-onset SpA and healthy controls were (132 ± 81 vs 122 ± 113; P = 0.439) and (27 ± 15 vs 39 ± 49; P = 0.985) respectively. The analysis did not show significant differences in serum levels of DKK-1 (P = 0.293), sclerostin (P = 0.428), and OPG (P = 0.504) between patients with SpA with juvenile onset and adult SpA. Conclusion In our study the juvenile onset of the disease did not correlate with the inhibitors of the Wnt signalling pathway and OPG in patients with SpA.

Serum DKK-1 level in ankylosing spondylitis: insights from meta-analysis and Mendelian randomization.

The purpose of this study was to precisely evaluate the serum Dickkopf-1 (DKK-1) level in patients with ankylosing spondylitis (AS) relative to that in normal controls and to test the causal relationship between DKK-1 and the risk of AS. Embase, PubMed, Web of Science, WANFANG DATA, VIP, and China National Knowledge Infrastructure (CNKI) were comprehensively searched until July 2022 for pertinent studies. The pooled standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated by the fixed or random-effect model. In Mendelian randomization (MR) analysis on the causal relationship between serum DKK-1 level and AS risk, the inverse variance weighting method (IVW), MR-Egger regression, weighted median method, and weighted pattern method were applied. Sensitivity analyses, including the horizontal pleiotropy test, heterogeneity test, and leave-one-out test, were also performed. The meta-analysis of 40 studies containing 2,371 AS patients and 1,633 healthy controls showed that there was no significant difference in DKK-1 serum level between AS patients and normal controls (pooled SMD=0.207, 95% CI =-0.418-0.832, P=0.516). The subgroup analysis of the CRP ≤ 10 mg/L group showed that AS patients had higher serum DKK-1 concentration than the healthy controls (SMD=2.267, 95% CI = 0.102-4.432, P=0.040). Similarly, MR analysis also demonstrated no significant association between DKK-1 serum level and AS (IVW OR=0.999, 95% CI = 0.989-1.008, P=0.800). All sensitivity analyses revealed consistent results. There was no significant change in serum DKK-1 concentration between AS patients and healthy controls. In addition, no causal relationship exists between serum DKK-1 levels and AS risk.

INCREASED SERUM SCLEROSTIN LEVEL IS A RISK FACTOR FOR PERIPHERAL ARTERY OCCLUSIVE DISEASE IN PATIENTS WITH HYPERTENSION

Objective: Sclerostin is associated with endothelial inflammation and vascular calcification and therefore contributes to atherosclerosis disease. Hypertension is one of risk factors of peripheral arterial occlusive disease (PAOD), is associated with increased mortality in patients with hypertension. The aim of this study was to determine the relationship between serum sclerostin level and PAOD in patients with hypertension. Design and method: Fasting blood samples and baseline characteristics were obtained from 92 hypertensive patients. ABI values were measured using an automated oscillometric device. Patients with ABIs of &lt;0.9 were categorized into the low ABI group. The serum sclerostin and dickkopf-1 (DKK1) concentrations were determined using commercially available enzyme-linked immunosorbent assays. Results: In total, 14 patients with hypertension (15.2%) were in the low ABI group. When compared to those in the normal ABI group, the low ABI group had high rates of diabetes mellitus (P = 0.044) as well as the high serum C-reactive protein levels (P = 0.001) and sclerostin levels (P &lt; 0.001), but the serum DKK1 level did not find this association (P = 0.639). The multivariable logistic regression analysis revealed that serum levels of sclerostin (odds ratio [OR]: 1.052, 95% confidence interval [CI]: 1.018–1.088, P = 0.002) was independently associated with PAD in patients with hypertension. Conclusions: Serum levels of sclerostin, but not DKK1, were associated with PAOD in patients with hypertension.

Anti-tumor necrosis factor alpha treatment does not influence serum levels of the markers associated with radiographic progression in ankylosing spondylitis.

The study aimed to determine the levels of change of the markers related to radiographic progression, such as Dickkopf-1 (DKK-1), sclerostin (SOST), bone morphogenetic protein (BMP)-2 and -4, and interleukin (IL)-17 and -23, in ankylosing spondyloarthritis (AS) during anti-tumor necrosis factor alpha (TNF-α) treatment. Fifty-three anti-TNF-α naïve AS patients (34 males, 19 females; median: 38 years; range, 20 to 52 years) refractory to conventional treatments meeting the modified New York criteria or Assessment of SpondyloArthritis International Society classification criteria were enrolled to this cross-sectional, controlled study between October 2015 and January 2017. Fifty healthy volunteers (35 males, 15 females; median: 36 years; range, 18 to 55 years) with similar age and sex characteristics were recruited. Serum DKK-1, BMP-2, BMP-4, SOST, IL-17, and IL-23 levels were measured in both groups. The serum levels of the markers were measured again after about two years (mean follow-up duration of 21.7±6.4 months) in AS patients who started anti-TNF-α treatment. Demographic, clinical characteristics, and laboratory parameters were recorded. The disease activity at the time of inclusion was assessed through the Bath Ankylosing Spondylitis Disease Activity Index. Serum DKK-1, SOST, IL-17, and IL-23 levels in the AS group before anti-TNF-a treatment were significantly higher compared to the control group (p<0.01 for DKK-1, p<0.001 for others). There was no difference regarding serum BMP-4 levels, whereas BMP-2 levels were significantly higher in the control group (p<0.01). Forty (75.47%) AS patients had serum marker levels measured after anti-TNF-α treatment. No significant change was observed in the serum levels of these 40 patients measured 21.7±6.4 months after the initiation of anti-TNF-α treatment (p>0.05 for all). In AS patients, there was no change in DKK-1/SOST, BMP, and IL-17/23 cascade with anti-TNF-α treatment. This finding may suggest that these pathways act independently of each other, and their local effects are not influenced by systemic inflammation.

Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease.

Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson's linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.

Circulating Dickkopf1 Parallels Metabolic Adaptations and Predicts Disease Trajectories in Patients With COVID-19.

Background and aimsCoronavirus disease 19 (Covid-19) trajectories show high interindividual variability, ranging from asymptomatic manifestations to fatal outcomes, the latter of which may be fueled by immunometabolic maladaptation of the host. Reliable identification of patients, who are at risk of severe disease remains challenging. We hypothesized that serum concentrations of Dickkopf1 (DKK1) indicate disease outcomes in SARS-CoV-2 infected individuals.MethodsWe recruited hospitalized patients with PCR-confirmed SARS-CoV-2 infection and included 80 individuals, for whom blood samples from two independent time points were available. DKK1 serum concentrations were measured by ELISA in paired samples. Clinical data was extracted from patient charts and correlated with DKK1 levels. Publicly available datasets were screened for changes in cellular DKK1 expression upon SARS-CoV-2 infection. Plasma metabolites were profiled by NMR spectroscopy in an unbiased fashion and correlated with DKK1 data. Kaplan Meier and Cox regression analysis were used to investigate the prognostic value of DKK1 levels in the context of Covid-19.ResultsWe report that serum levels of DKK1 predict disease outcomes in patients with Covid-19. Circulating DKK1 concentrations are characterized by high interindividual variability and change as a function of time during SARS-CoV-2 infection, which is linked to platelet counts. We further find that the metabolic signature associated with SARS-CoV-2 infection resembles fasting metabolism and is mirrored by circulating DKK1 abundance. Patients with low DKK1 levels are twice as likely to die from Covid-19 than those with high levels and DKK1 predicts mortality independent of markers of inflammation, renal function and platelet numbersConclusionOur study suggests a potential clinical use of circulating DKK1 as a predictor of disease outcomes in patients with Covid-19. These results require validation in additional cohorts.

Decreased Serum Dickkopf-1 Levels After Hypoglycemic Therapy in Patients with Type 2 Diabetes Mellitus.

AimDickkopf-1 (DKK-1) is a major inhibitor of Wingless protein signaling pathway, which is involved in glucose metabolism and cardiovascular diseases. The aim of the study was to investigate the changes of serum DKK-1 levels after hypoglycemic treatments and the relationship between DKK-1 and clinical parameters.Materials and MethodsThe study was a sub-study of a previously published clinical trial (the effect of Acarbose on glycemic variability in patients with type 2 diabetes mellitus using premixed insulin compared to metformin). All subjects underwent anthropometric and biochemical assessments at baseline and endpoint. Serum DKK-1 levels of 92 subjects were measured at baseline and after 12-week hypoglycemic treatment.ResultsDKK-1 levels were significantly decreased after hypoglycemic treatment for 12 weeks (P < 0.001). ΔDKK-1 levels were not correlated with improvement of metabolic parameters (all P > 0.05) but were negatively correlated with baseline DKK-1 levels (r = −0.263, P = 0.011). Spearman correlation showed that baseline DKK-1 levels were positively related to baseline total cholesterol (r = 0.226, P = 0.030) and low-density lipoprotein cholesterol (LDL-C) (r = 0.277, P = 0.007). Compared with the higher baseline DKK-1 group (≥3700 pg/mL), subjects in the lower baseline DKK-1 group (<3700 pg/mL) had significantly lower baseline glycated hemoglobin A1c levels (P = 0.008) and LDL-C levels (P = 0.048). Systolic and diastolic pressure were decreased more significantly in the lower baseline DKK-1 group than that in the higher baseline DKK-1 group (both P < 0.05).ConclusionSerum DKK-1 levels were decreased after hypoglycemic treatments. Patients with lower baseline DKK-1 levels were featured by more favorable cardiometabolic factors.

Assessment of Serum Levels of the WNT Pathway Antagonist (Dickkopf-1) in a Sample of Type 2 Diabetic Patients with Retinopathy using Two Groups of Antidiabetics

Objectives: Dickkopf-1 (DKK-1) is WNT/b-catenin pathway antagonist which plays a detrimental role in the development of diabetic retinopathy (DR). This research aimed to assess serum DKK-1 levels in diabetic patients who have and have not developed DR and, compare them with the control subjects finding out whether we can use it as an indicator for DR early diagnosis and to find out which one of the widely used two groups of antidiabetic treatments had the greater effect on this biomarker and hence on the progression of DR. Methods: The study participants were divided into two subgroups: First, 70 patients (36 male, 34 female) with type 2 diabetes mellitus, among them 35 patients diagnosed with DR and 35 with no evidence of DR, and secondly, non-diabetic controls (11 male, 9 female) were selected from the patients attending Ibn AL-Haitham hospital for ophthalmology and a specialized center for endocrinology and diabetes. Venous blood samples of all participants were drawn after an overnight fast, and serum samples were stored at -20ºC until DKK-1 assay. Results: Serum DKK-1 showed significantly lower levels in diabetic patients with (6.1 ± 2 ng/mL) or without DR (14 ± 6.2 ng/mL) when compared to those of controls (34 ± 12.25 ng/mL) (p 0.05). Furthermore, serum DKK-1 levels were lower in the late stage of DR compared to the early stage 5.6 ± 1.7 and 7 ± 1.9 ng/mL, respectively. Furthermore, DPP-4 inhibitors cause a better increment in DKK-1 levels when compared to SU in the NDR group. Conclusions: Reduced serum levels of DKK-1 are related to the existence and worsening of DR and have the prospect to serve as an indicator for this condition.

DKK1 Positively Correlates with Lung Function in COPD Patients and Reduces Airway Inflammation.

PurposeWNT/β-catenin signal pathway is a potential hope for lung tissue repair. We investigated the levels of Dickkopf‐1 (DKK1), an endogenous inhibitor of WNT/β-catenin signal pathway, in chronic obstructive pulmonary disease (COPD) patients and airway inflammation.Patients and MethodsCollected the demographic and clinical characteristics of 36 healthy controls, 25 stable COPD patients and 10 acute exacerbation of COPD (AECOPD) patients, then performed pulmonary function and detected serum DKK1 levels. After over-expression of DKK1, detect the levels of DDK1, lipoprotein-related protein 6 (LRP6) and inflammatory factors in bronchial epithelial cells stimulated with cigarette smoke extract (CSE).ResultsSerum DKK1 were reduced in stable COPD patients compared to healthy controls (3866.72 ± 775.33 pg/mL vs 5317.61 ± 1317.20 pg/mL, p<0.0001), but there was no significant difference between stable and acutely exacerbated patients (3866.72 ± 775.33 pg/mL vs 3482.10 ± 841.25 pg/mL, p>0.05). DKK1 was positively correlated with FEV1 (r = 0.570, p<0.0001), FEV1/FVC (rho = 0.590, p<0.0001), FEV1/Pre (r = 0.517, p<0.0001). Multiple linear regression analysis also suggested that FEV1 levels were higher with increasing DKK1. In vitro, elevated IL-6, IL-8, TNF-α and decreased DKK1, LRP6 were found in Beas-2B cells after CSE treatments, and increased LRP6 and decreased inflammatory factors were found after overexpression of DKK1. Andrographolide restored the CSE-induced decrease in DKK1 and increase in IL-6 and IL-8.ConclusionDKK1 levels were decreased in COPD patients and positively correlated with lung function, overexpression of DKK1 and andrographolide attenuated airway cell inflammation, both suggesting a potential role in pathophysiology and providing a disease-specific biomarker pattern.

Hyperbaric Oxygen Therapy Does Not Have a Negative Impact on Bone Signaling Pathways in Humans.

Introduction: Oxygen is emerging as an important factor in the local regulation of bone remodeling. Some preclinical data suggest that hyperoxia may have deleterious effects on bone cells. However, its clinical relevance is unclear. Hence, we studied the effect of hyperbaric oxygen therapy (HBOT) on serum biomarkers reflecting the status of the Wnt and receptor activator of NF-κB ligand (RANKL) pathways, two core pathways for bone homeostasis. Materials and methods: This was a prospective study of 20 patients undergoing HBOT (mean age 58 yrs., range 35–82 yrs.) because of complications of radiotherapy or chronic anal fissure. Patients were subjected to HBOT (100% oxygen; 2.4 atmospheres absolute for 90 min). The average number of HBOT sessions was 20 ± 5 (range 8–31). Serum hypoxia-inducible factor 1- (HIF1-, osteoprotegerin (OPG), RANKL, and the Wnt inhibitors sclerostin and dickkopf-1 (DKK1) were measured at baseline and after HBOT by using specific immunoassays. Results: HIF-1α in eight patients with measurable serum levels increased from 0.084 (0.098) ng/mL at baseline to 0.146 (0.130) ng/mL after HBOT (p = 0.028). However, HBOT did not induce any significant changes in the serum levels of OPG, RANKL, sclerostin or DKK1. This was independent of the patients’ diagnosis, either neoplasia or benign. Conclusion: Despite the potential concerns about hyperoxia, we found no evidence that HBOT has any detrimental effect on bone homeostasis.

Comparison of Maternal Serum Levels and Placental mRNA Levels of Dickkopf-1 in Preeclamptic and Normal Pregnant Women at Delivery.

Background Preeclampsia remains a major cause of perinatal and maternal mortality and morbidity worldwide. Wnt/β-catenin signaling is known to be critically involved in placenta development processes. Dickkopf-1 (DKK1) is a key regulator of this transduction pathway. The aim of this study is to compare maternal serum DKK1 levels and placental mRNA levels of DKK1 and β-catenin in preeclamptic and normal pregnant women at delivery. Methods The present study included 30 women with preeclampsia and 30 women with normal pregnancy. Maternal serum DKK1 levels were measured by ELISA. Placental mRNA levels of DKK1 and β-catenin were detected using RT-PCR. Results Decreased maternal serum DKK1 levels were associated with worse maternal and fetal complications including HELLP syndrome, determination of one or more pathological symptom and IUGR diagnosis. No significant difference in maternal serum DKK1 levels was reported between preeclamptic women and women with normal pregnancy. Placental mRNA DKK1 levels were lower in preeclamptic women compared with normal pregnant women. Placental mRNA β-catenin levels showed no significant difference between two groups. Conclusions Our findings reported the aberrant placental mRNA DKK1 levels in patients with preeclampsia. In addition, worse preeclampsia features were associated with decreased maternal serum DKK1 levels. Hence, aberrant Wnt/β-catenin signaling might present a plausible mechanism in preeclampsia pathogenicity. Dysregulated expression of DKK1 at gene level in the placenta but not at protein level in the maternal serum might confirm the notion that preeclampsia is a type of placenta-derived disease.

Linking extracellular inhibitors of Wnt/beta-catenin signaling to carotid intima-media thickness in heart failure with reduced ejection fraction

Abstract Background The Wnt/β-catenin signaling pathway plays an important role in endothelial inflammation, vascular calcification, contributing to atherosclerosis development and progression. Sclerostin and Dickkopf-1 (DKK-1) are soluble extracellular canonical Wnt signaling inhibitors frequently associated with atherosclerotic disease. Purpose We investigated the possible association between carotid intima-media thickness (cIMT) and circulating levels of sclerostin and DKK-1 in patients with heart failure with reduced ejection fraction (HFrEF). Methods 65 patients with HFrEF were assigned to one of two groups based on cIMT measurements: 30 patients had normal cIMT, whereas 35 patients showed pathological cIMT. CIMT was assessed by vascular ultrasonography, and values above 0.9 mm were considered abnormal. Serum sclerostin and DKK-1 levels were measured using commercially available ELISA kits. Unpaired t-test and Mann-Whitney test were used for statistical analysis (p&amp;lt;0.05 was considered statistically significant). Results Patients belonging to the group with abnormal cIMT were older (70±9 years vs. 57±12 years, p&amp;lt;0.0001), had higher systolic blood pressure (123±16 mm Hg vs. 112±15 mm Hg, p=0.005), and had more often type 2 diabetes mellitus (40.00% vs. 13.33%, p=0.017). Sclerostin levels were significantly higher in the abnormal cIMT population (537.91±816.69 pg/mL vs. 276.37±173.21 pg/mL, p=0.017), whereas serum DKK-1 concentrations did not differ significantly (398.34±218.73 pg/mL vs. 352.35±188.08 pg/mL, p=0.498). The two groups had similar C-reactive protein levels (1.78±2.77 mg/dL vs. 1.88±2.77 mg/dL, p=0.200), estimated glomerular filtration rates (73.60±22.32 mL/min/1.73m2 vs. 66.25±23.69 mL/min/1.73m2, p=0.254) and body mass index (27.58±4.95 kg/m2 vs. 26.65±5.75 kg/m2, p=0.490). Conclusion Patients with HFrEF and increased cIMT had elevated levels of serum sclerostin. DKK-1 levels did not increase with the progression of cIMT. Further studies with large sample size are needed to establish the involvement of these proteins in vascular calcification and atherosclerosis in the setting of HFrEF. Funding Acknowledgement Type of funding sources: None.

Assessment of Serum sRANKL, sRANKL/OPG Ratio, and Other Bone Turnover Markers with the Estimated 10-Year Risk of Major and Hip Osteoporotic Fractures in Rheumatoid Arthritis: A Cross-Sectional Study.

Background Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. Methods Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. Results The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). Conclusion High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.

Effect of androgen deprivation therapy on serum levels of sclerostin, Dickkopf-1, and osteoprotegerin: a cross-sectional and longitudinal analysis

Androgen deprivation therapy (ADT) for men with prostate cancer (PCa) results in accelerated bone loss and increased risk of bone fracture. The aim of the present study was to evaluate serum bone markers—sclerostin, Dickkopf-1 (DKK-1) and osteoprotegerin (OPG), in a cohort of 88 PCa patients without known bone metastases, managed with and without ADT, and to analyse their relationship with bone mineral density (BMD) and sex steroids. The cross-sectional analysis between acute-, chronic- and former-ADT groups and PCa controls showed that sclerostin and OPG levels significantly differed between them (p = 0.029 and p = 0.032). Groups contributing to these significant changes were recorded. There were no significant differences in serum DKK-1 levels across the four groups (p = 0.683). In the longitudinal analysis, significant % decreases within groups were seen for DKK-1 [chronic-ADT (− 10.06%, p = 0.0057), former-ADT (− 12.77%, p = 0.0239), and in PCa controls group (− 16.73, p = 0.0022); and OPG levels in chronic ADT (− 8.28%, p = 0.003) and PCa controls group (− 12.82%, p = 0.017)]. However, % changes in sclerostin, DKK-1, and OPG did not differ significantly over 6-months across the evaluated groups. Sclerostin levels showed significant positive correlations with BMD at baseline in the ADT group, while in PCa controls this correlation existed at both baseline and 6-month time points. Sclerostin correlated negatively with testosterone in former ADT users and in PCa controls. Possible prognostic features denoted by parallel increases in sclerostin and BMD are discussed.