Serum Levels Of Dickkopf-1 Research Articles

Serum Dickkopf-1 as A Biomarker for The Diagnosis and Prognosis of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma is one of the commonest cancers in world. It is one of the major health problems and its incidence is increasing. The main routinely used parameter for diagnosis of HCC is AFP, also it can be elevated in the liver cirrhosis. It represents a liver cell specific, not a tumor specific marker, for these reasons, we suggest use AFP as a supplementary marker for HCC diagnosis. So, identification of a sensitive biomarker to improve early diagnosis of HCC is in need. Aim of the work: this study was aimed to evaluate the clinical significance of serum Dickkopf-1 (DKK1) as a diagnostic and prognostic marker in hepatocellular carcinoma. Patients and Methods: in this study 100 subjects were included and divided into 3 groups, Group I: included 50 patients with HCC, and divided into 2 subgroups according to Barcelona Clinic Liver Cancer (BCLC) into early HCC (24 patients) and late HCC (18 patients). Group II: included 25 patients with liver cirrhosis. Group III: included 25 healthy subjects (control). Clinical assessment, routine laboratory evaluation, CT scan and measurements of serum alpha-fetoprotein (AFP) and DKK1 were performed to all patients and repeated to group I patients 1 month after treatment. Results: the current study showed that Serum DKK1 was significantly elevated in HCC group compared to liver cirrhosis and healthy control groups, with increased level in late than early stage. The optimum cut off values of DKK1 for diagnosis of HCC was 1.92 ng/mL (AUC 0.926, sensitivity 88% and specificity 83%). While the optimum cut off value for AFP was 102 ng/mL (AUC 0.904, 71% sensitivity and 84% specificity). Testing of both serum DKK1 and AFP increased the diagnostic accuracy for HCC (AUC 0.964, sensitivity 91%, and specificity 90%). Serum DKK1 level significantly decreases after HCC treatment with radio-frequency ablation. Conclusion: It could be concluded that Testing of both serum DKK1 and AFP significantly increased the diagnostic accuracy for HCC. Meanwhile, DKK1 can be used alone for diagnosis of HCC even in HCC with inconclusive AFP. Serum DKK1 might be a potential diagnostic and prognostic marker for HCC.

Sclerostin rather than Dickkopf-1 is associated with mSASSS but not with disease activity score in patients with ankylosing spondylitis.

To determine the serum levels of Dickkopf-1 (DKK-1) and sclerostin, as well as their correlations with the structural damage assessed by modified stoke ankylosing spondylitis spine score (mSASSS) and the disease activity evaluated by ankylosing spondylitis disease activity score (ASDAS) in patients with ankylosing spondylitis (AS). Eighty-eight AS patients, 26 rheumatoid arthritis (RA) patients, and 26 age- and gender-matched healthy controls (HC) were collected from rheumatic clinic of the Second Affiliated Hospital of Zhejiang University, School of Medicine, between March 2015 and July 2015. Demographic data, parameters of ASDAS, and image evaluations of spine (i.e., mSASSS) were collected. The serum levels of DKK-1 and sclerostin were measured using commercially available ELISA kits. Both DKK-1 and sclerostin were significantly higher in the AS patients than in the controls (1855 ± 84.58 vs. 1406 ± 99.76pg/ml and 106 ± 6.75 vs. 62.78 ± 6.39pmol/l, respectively, P < 0.05). The correlation analysis suggested a negative correlation between serum sclerostin and mSASSS (P = 0.019, r2 = 0.062). DKK-1 had a trend of positive correlation with mSASSS, but was not statistically significant (P > 0.05). There was no association between the serum levels of DKK-1 or sclerostin and disease activity assessed by ASDAS (P > 0.05). DKK-1 and sclerostin had a negative correlation (P = 0.013, r2 = 0.07). In the present study, the expressions of serum DKK-1 and sclerostin were independent of disease activity. Sclerostin was negatively correlated with the mSASSS, which suggests that sclerostin may be a potential marker indicating the spine ossification process in AS. The specific mechanism remains to be investigated.

Dickkopf-1 (Dkk-1) serum levels in systemic sclerosis and rheumatoid arthritis patients: correlation with the Trabecular Bone Score (TBS).

The aim of this research was to determine any correlations between Dickkopf-1 serum levels (Dkk-1, a natural inhibitor of the Wnt signaling pathway promoting osteoclastogenesis) and the Trabecular Bone Score (TBS), in systemic sclerosis (SSc) and rheumatoid arthritis (RA) patients. It also aimed at determining any difference in Dkk-1 serum levels between SSc and RA patients and a control group (CNT) of healthy subjects. A prospective study was carried out in 60 SSc and 60 RA patients and 60 CNT. Dkk-1 serum levels were evaluated by the ELISA method (Quantikine Human Dkk-1 Immunoassay, R&D System, Minneapolis, USA). The severity of microvascular damage was evaluated by nailfold videocapillaroscopy (NVC patterns: "Early," "Active," "Late"), in the SSc patients. TBS analysis and bone mineral density (BMD, g/cm2) were measured in all patients/subjects. The SSc patients showed higher Dkk-1 serum levels than RA (p < 0.004) and CNT (p < 0.0001) patients. SSc patients, showing the "Late" NVC pattern had statistically higher Dkk-1 serum levels than patients with either the "Active" or "Early" (p < 0.004) patterns. Only in the "Late" NVC pattern group of SSc patients was there a significant negative correlation between Dkk-1 and TBS values (p < 0.0001). The increased Dkk-1 serum levels and decreased TBS values observed suggest a diffuse bone damage in SSc patients with advanced disease, as demonstrated by the concomitant presence of the "Late" NVC pattern. Moreover, the bone remodeling in SSc seems even higher than that in RA patients.

Systemic Alterations of Wnt Inhibitors in Patients with Prostate Cancer and Bone Metastases.

Purpose Dickkopf-1 (DKK-1) and sclerostin seem to inhibit osteoblast activity by blocking the Wnt pathway, which leads to progression of metastatic prostate cancer (PC). However, it is unknown whether serum levels of these proteins are altered in PC patients with or without metastasis. The aim of this study was to assess DKK-1 and sclerostin serum levels in PC patients, including patients with bone metastases. Methods The study cohort (N = 143) consisted of 53 controls with benign prostatic hyperplasia (BPH), 43 with localized PC (PC cM0), and 47 had PC with metastasis (PC cM1). Serum levels of DKK-1 and sclerostin were measured by enzyme-linked immunosorbent assay. Results were compared using the Kruskal-Wallis tests; post hoc analysis was performed using the Tukey-Kramer test. Results Mean DKK-1 levels in patients with BPH (2809.4 pg/ml) (p < 0.001) as well as PC cM1 (2575.5 pg/ml) (p = 0.001) were significantly higher than in patients with PC cN0 cM0 (1551.8 pg/ml). Among PC cM1 patients, median DKK-1 levels were significantly lower in patients with castration-resistant disease compared to those with hormone-sensitive PC (p = 0.02); in contrast, sclerostin concentrations were elevated (p = 0.04). DKK-1 correlated with PSA in the cM1 group (p = 0.03) and sclerostin correlated with PSA in the PC group (0.01). Conclusions DKK-1 is involved in the progression of PC. DKK-1-mediated inhibition of osteoblasts, which contributes to tumor progression and osteolytic metastases, may also play a role in the development of metastases with osteoblastic features. The use of DKK-1 antibodies should be considered for studies including metastatic PC patients.

Parathyroid hormone is a determinant of serum Dickkopf-1 levels in ankylosing spondylitis.

Available studies reported contradictory results about serum levels Dickkopf-1 (DKK1), an inhibitor of Wnt signaling in patients with ankylosing spondylitis (AS). In previous studies, we observed in other conditions that parathyroid hormone (PTH) serum levels were an important determinant of DKK1 serum levels. The aim of the present study was to investigate it in patients with AS. We recruited 71 patients diagnosed with AS. Levels of C-reactive protein (CRP), DKK1, PTH, 25OH-vitamin D, and bone turnover markers (intact N-propeptide of type I collagen, P1NP, and C-terminal telopeptide of type I collagen, CTX) were measured and compared to healthy controls (HC). Dual X-ray absorptiometry at lumbar spine and proximal femoral site was used for bone mineral density (BMD) assessment and spine X-rays were also performed. PTH serum levels were found to be significantly higher in AS patients than in HC (33.8 ± 14.11 vs 24.8 ± 13pg/ml, p = 0.002), while mean DKK1 serum levels were lower than in HC (23.3 ± 13.1 vs 29.8 ± 15.9pmol/l, p = 0.009). A positive correlation between DKK1 and PTH (correlation coefficient + 0.25, p = 0.03) was observed; it remained significant in a multivariate analysis. In patients with longer disease duration, DKK1 was also positively correlated with CTX (coefficient 0.42, p = 0.01), and PTH was higher in those patients with low BMD (Z-score ≤ - 1) at any site (p = 0.04). Also in AS, PTH is an important determinant of DKK1 serum levels and should be evaluated in studies on DKK1. PTH might have a role in bone involvement in AS, also through the Wnt pathway.

Carbamazepine, Sodium Valproate and Levetiracetam Modulate Wnt Inhibitors in Indian Women with Epilepsy

Background: Antiepileptic drug (AED) therapy has been claimed to deteriorate bone health. Majority of the research was inclined towards vitamin-D deficiency as the patho-mechanism. However, after the role of Wnt in bone metabolism was discovered, it has paved way for investigating the role of Wnt inhibitors in mediating effects on bone accrual. Recently, we have reported the modulation of two Wnt inhibitors, sclerostin and dickkopf-1 (DKK-1), following AED therapy in Indian women with epilepsy, however, the subgroup analysis for individual drug is elucidated in this report. Methods: Individual analysis for our earlier cross-sectional study on three AEDs, carbamazepine (CBZ), sodium valproate (SVP) and levetiracetam (LTM), on sclerostin and dickkopf-1, and their correlation with receptor activator of nuclear factor kappaB ligand (RANKL) and serum 25-hydroxy vitamin D (25OHD) was assessed in Indian women with epilepsy. Results: We observed enhanced sclerostin and 25OHD levels with all three AEDs while serum RANKL was higher with SVP and LTM only. Further, serum DKK-1 levels were lowered with CBZ and LTM. Sclerostin showed a positive correlation with RANKL in CBZ group, while DKK-1 presented no such relationship. Conclusion: As sclerostin is more specific than DKK-1, we may conclude that these drugs may compromise bone health through disturbance in Wnt signaling mechanisms.

Supervised learning reveals circulating biomarker levels diagnostic of hepatocellular carcinoma in a clinically relevant model of non-alcoholic steatohepatitis; An OAD to NASH.

Although cirrhosis is a key risk factor for the development of hepatocellular carcinoma (HCC), mounting evidence indicates that in a subset of patients presenting with non-alcoholic steatohepatitis (NASH) HCC manifests in the absence of cirrhosis. Given the sheer size of the ongoing non-alcoholic fatty liver disease (NAFLD) epidemic and the dismal prognosis associated with late-stage primary liver cancer there is an urgent need for HCC surveillance in the NASH population. Using serum levels of HCC biomarkers as vectors and biopsy-proven HCC or no HCC as outputs / binary classifier, a supervised learning campaign was undertaken to develop a minimally invasive technique for making a diagnosis of HCC in a clinically relevant model of NASH. Adult mice randomized to control diet or a fast food diet (FFD) were followed for up to 14 mo and serum level of a panel of HCC-relevant biomarkers was compared with liver biopsies at 3 and 14 mo. Both NAFLD Activity Score (NAS) and hepatic hydroxyproline content were elevated at 3 and 14 mo on FFD. Picrosirius red staining of liver sections revealed a filigree pattern of fibrillar collagen deposition with no cirrhosis at 14 mo on FFD. Nevertheless, 46% of animals bore one or more tumors on their livers confirmed as HCC in hematoxylin-eosin-stained liver sections. In this training set, receiver operating characteristic (ROC) curves analysis for serum levels of the HCC biomarkers osteopontin (OPN), alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) returned concordance-statistic/area under ROC curve of ≥ 0.89. Serum levels of OPN (threshold, 218 ng/mL; sensitivity, 82%; specificity, 86%), AFP (136 ng/mL; 91%; 97%) and DKK1 (2.4 ng/mL; 82%; 81%) diagnostic for HCC were confirmed in a test set comprising mice on control diet or FFD and mice subjected to hepatic ischemia-reperfusion injury. These data suggest that levels of circulating OPN, AFP and DKK1 can be used to make a diagnosis of HCC in a clinically relevant model of NASH.

Changes in expression of Wnt signaling pathway inhibitors dickkopf-1 and sclerostin before and after total joint arthroplasty.

The aim is to study how serum concentration of Dickkopf-1 (DKK1) and Sclerostin (SOST) varies in patients before and after undergoing total joint arthroplasty (TJA). A total of 104 patients undergoing TJA were included in this study. Serum DKK1 and SOST were measured at 1 day before and 1, 3, and 5 days after surgery. DKK1 levels were highest at 5 days’ postoperation, increasing to 25.17% above preoperation levels (P < .01), while SOST levels were lowest at 3 days’ postoperation, falling to 18.71% below preoperation levels (P < .05). Serum levels of DKK1 and SOST showed opposite trends in the days following TJA. Our research describes for the first time the perioperative changes observed in serum DKK1 and SOST levels of osteoarthritis (OA) patients undergoing TJA. Increased DKK1 and decreased SOST levels may help maintain the equilibrium of the WNT pathway in OA patient's postsurgery.

Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin, and TNF-α in knee osteoarthritis patients.

Knee osteoarthritis (KOA) is a common degenerative joint disease causing pain, stiffness, reduced motion, swelling, crepitus, and disability. Several inflammatory markers and cartilage degradation products can be used as biomarkers in OA. The key factors of bone metabolism in normal joint bone, dickkopf-1 (DKK1) and osteoprotegerin (OPG), interact with Wnt signaling pathway, balancing between bone absorption and bone reconstruction. TNF-α is a key inducer of DKK-1, which belongs to the family of proteins involved in joint remodeling. The present study compared the serum levels of DKK1, TNF-α, and OPG in patients with KOA and healthy controls to analyze the interrelationship and the severity of joint destruction. One hundred forty-eight patients with KOA and 101 healthy controls were enrolled in this study. Anteroposterior knee radiographs determined the severity of the disease in the affected knee. The radiographic grading of KOA was performed by the Kellgren-Lawrence criteria. Serum levels of DKK-1, TNF-α, and OPG were estimated using the multiplex particle-based flow cytometry. Higher serum levels of OPG and TNF-α were observed in KOA than the controls; KOA patients showed a lower serum level of DKK-1, whereas the serum levels of DKK1 correlated with the progression of KOA. The serum levels of TNF-α, OPG, and DKK-1 correlated with incident KOA. In the ROC curve analysis, DKK1 levels showed 78.6% sensitivity and 40% specificity, TNF-α levels showed 74.1% sensitivity and 76.0% specificity, and OPG showed 88.1% sensitivity and 81% specificity in predicting severe KOA. In the univariate and multivariate analyses, TNF-α and OPG emerged as independent predictors of severe KOA. This study, for the first time, combined TNF-α, DKK1, and OPG as valuable biological markers in predicting the severity of KOA radiographically in the clinic. This study also supported the inflammation-induced DKK1 and OPG in OA pathogenesis.

Association between serum dickkopf-1 levels and disease duration in axial spondyloarthritis

BackgroundAxial spondyloarthritis (axSpA) is characterized by new bone formation. The complex systems underlying this process involve Wnt-signaling pathway. It has been observed that serum levels of dickkopf-1 (DKK-1), an important inhibitor of Wnt-signaling, are decreased in patients with axSpA. However, these data are from studies including only patients with long-standing disease.The aim of this study is to investigate if symptom duration influences on serum DKK-1 levels in patients with axSpA. Material and methodsA cross-sectional study including consecutive patients with axSpA (ASAS criteria) naïve for anti-TNF therapy. Collected data included demographic and disease characteristics, time since first symptom onset, assessment of disease activity and function, and determination of DKK-1 serum levels. Patients were classified as early axSpA (symptom duration ≤5 years) and established axSpA (>5 years). Linear regression models were employed to investigate the variables related to DKK-1 serum levels. ResultsIn total, 90 patients were included. Sixty-eight patients had early axSpA and 22 had established disease. Serum levels of DKK-1 were significantly higher in patients with early axSpA compared with established axSpA (22.1±12.6 vs 16.4±10.7pM; p=0.04). Among all tested variables, only symptom duration was significantly and inversely correlated with DKK-1 serum levels (beta: −0.041; p=0.01). ConclusionSerum DKK-1 levels in axSpA depend on disease duration. As disease duration increases, DKK-1 serum levels decrease. Based on this, an intensive treatment at early stages of the disease could have a better outcome on inhibiting/slowing radiographic progression in patients with axSpA.

Adjuvant tamoxifen but not aromatase inhibitor therapy decreases serum levels of the Wnt inhibitor dickkopf-1 while not affecting sclerostin in breast cancer patients.

Endocrine therapies, including tamoxifen or aromatase inhibitors, are indispensable for the treatment of patients with estrogen receptor (ER)- and/or progesterone-positive breast cancer. Whereas tamoxifen displays partial ER agonistic effects in bone, aromatase inhibitors increase bone resorption and fracture risk. The Wnt inhibitors dickkopf-1 (DKK-1) and sclerostin negatively impact bone formation and are considered targets for the treatment of bone disorders. However, the effect of endocrine therapies on serum DKK-1 and sclerostin levels in patients with primary breast cancer remains elusive. Serum DKK-1 and sclerostin levels were measured at primary diagnosis as well as 3-5days and 12months after surgery in a cohort of 45 pre- and postmenopausal women with primary estrogen receptor-positive breast cancer treated with adjuvant tamoxifen or aromatase inhibitors. Mean baseline levels±SD for DKK-1 and sclerostin were 29.7±14.6 and 27.1±16.2pmol/l, respectively. A significant negative correlation of DKK-1 levels and age was observed (r=-0.32; p<0.05), but not for sclerostin. Of note, DKK-1 levels were significantly lower in peri- and postmenopausal women compared to premenopausal patients (-47%; p<0.05). In tamoxifen-treated patients, DKK-1 levels were reduced by 35% (p<0.01) one year after surgery but remained unaltered in patients treated with aromatase inhibitors. No significant changes were observed for sclerostin. DKK-1 serum levels were reduced in breast cancer patients receiving an adjuvant therapy with tamoxifen, possibly contributing to its bone-protective properties.

Serum Dickkopf-1 acts as a new biomarker in human breast cancer.

The serum levels of Dickkopf-1 (DKK1), a secreted Wnt family protein, are different in patients suffering various types of cancers. In the present study, we aim to explore the diagnostic value of DKK1 as a new biomarker in breast cancer. Serum was collected from 38 patients with breast cancer and 23 healthy controls. Serological levels of DKK1 were examined by enzyme-linked immunosorbent assay (ELISA). Significance and diagnostic performance including receiver operator characteristic (ROC) and areas under the curve were determined by SPSS software. Serum level of DKK1 was significantly increased in breast cancer patients compared to the healthy controls (P˂0.05). The expression levels of CA15-3 were also evaluated in patients suffering from breast cancer in comparison with healthy controls (P˂0.05). AUC for DKK1 and CA15-3 were 0.81 and 0.64 respectively. Sensitivity and specificity of DKK1 were more than CA15-3 in earlier stage of breast cancer. DKK1 expression in HER-2, estrogen receptor (ER) and progesterone receptor (PR) positive patients was decreased compared with HER-2, ER and PR negative patients. We found that the expression level of DKK1 in serum was increased in breast cancer patients, suggesting that serum expression level of DKK1 could be a useful biomarker in breast cancer.

High Sclerostin and Dickkopf-1 (DKK-1) Serum Levels in Children and Adolescents With Type 1 Diabetes Mellitus.

Childhood type 1 diabetes mellitus (T1DM) is associated with decreased bone mass. Sclerostin and dickkopf-1 (DKK-1) are Wnt inhibitors that regulate bone formation. To evaluate sclerostin and DKK-1 levels in T1DM children and to analyze the influence of glycemic control on bone health. Cross-sectional study conducted at a clinical research center. One hundred and six T1DM subjects (12.2 ± 4 years), 66 on multiple daily injections (MDIs) and 40 on continuous subcutaneous infusion of insulin (CSII), and 80 controls. The average bone transmission time (BTT) and amplitude-dependent speed of sound (AD-SoS) z scores were lower in patients with diabetes than in controls. Significantly increased DKK-1 (3593 ± 1172 vs 2652 ± 689 pg/mL; P < 0.006) and sclerostin (29.45 ± 12.32 vs 22.53 ± 8.29; P < 0.001) levels were found in patients with diabetes with respect to controls, particularly in patients on MDI compared with ones on CSII. Glycemic control was improved in CSII patients compared with MDI ones (P < 0.001) and was also associated with significantly higher BMI-SDS (P < 0.002) and BTT z scores (P < 0.02). With adjustment for age, multiple linear regression analysis of DKK-1 and sclerostin as dependent variables showed that levels of glycated hemoglobin, glucose, 25(OH) vitamin D, osteocalcin, and parathyroid hormone; years of diabetes; and BMI-SDS and AD-SoS z score were the most important predictors (P < 0.0001). Our study highlighted (1) the high serum levels of DKK-1 and sclerostin in T1DM children and their relationship with altered glycemic control and (2) the effect of CSII on improvement of glycemic control and bone health in T1DM children.

Abstract 3980: Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma

Abstract Esophageal squamous cell carcinoma (ESCC) can be treated effectively if diagnosed at an early stage. We evaluated whether measurement of Dickkopf-1 (DKK1) in combination of DKK1 autoantibodies in serum may benefit early diagnosis of ESCC. Serum DKK1 and DKK1 autoantibodies were measured by enzyme-linked immunosorbent assay in a training cohort (185 ESCC samples vs. 97 normal controls) and validated in a validation cohort (104 ESCC samples vs. 53 normal controls). Receiver operating characteristics (ROC) was applied to calculate diagnostic accuracy. The serum levels of DKK1 and DKK1 autoantibody were significantly higher in ESCC patients than in controls, respectively (P&amp;lt;0.0001). Measurement of serum DKK1 demonstrated an area under curve (AUC) of 0.709 [95% confidence interval (CI), 0.647-0.771], 37.3% sensitivity, and 90.7% specificity in the training set and an AUC of 0.697 (95% CI, 0.613-0.780), 41.3% sensitivity, and 84.9% specificity in the validation set. Testing of DKK1 and DKK1 autoantibodies together effectively improved the diagnostic accuracy for ESCC versus normal controls compared with either test alone (AUC 0.769, 95% CI 0.715-0.823, 50.3% sensitivity, and 90.7% specificity in the training cohort; AUC 0.752, 95% CI 0.675-0.829, 50.0% sensitivity, and 84.9% specificity in the validation cohort). Importantly, the diagnostic performance of the combination of DKK1 and DKK1 autoantibodies persisted in early ESCC patients (AUC 0.780, 95% CI, 0.699-0.862, 50.0% sensitivity, and 90.7% specificity in the training cohort; AUC 0.745, 95% CI, 0.626-0.865, 53.8% sensitivity, and 84.9% specificity in the validation cohort). Furthermore, the levels of serum DKK1 or DKK1 autoantibody after surgical resection were lower, respectively, compared with the corresponding preoperative samples (P&amp;lt;0.05). Our results suggest that measurement of DKK1 combined with DKK1 autoantibodies is a potentially valuable tool for the early detection of ESCC. Citation Format: Yu-Hui Peng, Yi-Wei Xu, En-Min Li, Li-Yan Xu. Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3980.

Increased Dickkopf-1 expression is correlated with poisoning severity in carbon monoxide-poisoned humans and rats

Context: Carbon monoxide (CO) poisoning results in neuronal injury. The expression of Dickkopf-1 (DKK-1) has not been investigated previously after CO poisoning.Objective: The current study aimed to investigate the DKK-1 expression levels in humans and rats with acute CO poisoning and to analyze their correlation with poisoning severity.Materials and methods: We measured serum DKK-1 levels in patients with acute CO poisoning (n = 94) and in healthy controls (n = 90). On admission, a poisoning severity score (PSS) was determined for each patient. In addition, 36 male Sprague–Dawley rats were randomly assigned into three groups: (a) Sham group, (b) Low CO group and (c) High CO group. At 2 h after CO poisoning, DKK-1 expression and histopathological damage in the hippocampal tissues were measured.Results: Serum DKK-1 levels were significantly higher in the acute CO-poisoned patients, compared to the healthy controls. Serum DKK-1 levels were significantly higher in the CO-poisoned patients with a lower PSS. In rats, CO poisoning induced significant upregulation of the gene and protein expression of DKK-1 in hippocampal tissues. Moreover, there was a positive correlation between DKK-1 levels and the degree of damage in the hippocampal tissues.Discussion: DKK-1 induction in neurons after CO poisoning causes further neuronal injury. The severity of acute CO poisoning in rat models is associated with elevated serum DKK-1 levels and its upregulation in the brain tissue.Conclusion: DKK-1 appears to have potential utility in providing valuable information for determining the severity and damage of CO poisoning.

Association between serum dickkopf-1 levels and disease duration in axial spondyloarthritis

BackgroundAxial spondyloarthritis (axSpA) is characterized by new bone formation. The complex systems underlying this process involve Wnt-signaling pathway. It has been observed that serum levels of dickkopf-1 (DKK-1), an important inhibitor of Wnt-signaling, are decreased in patients with axSpA. However, these data are from studies including only patients with long-standing disease.The aim of this study is to investigate if symptom duration influences on serum DKK-1 levels in patients with axSpA. Material and methodsA cross-sectional study including consecutive patients with axSpA (ASAS criteria) naïve for anti-TNF therapy. Collected data included demographic and disease characteristics, time since first symptom onset, assessment of disease activity and function, and determination of DKK-1 serum levels. Patients were classified as early axSpA (symptom duration ≤5 years) and established axSpA (>5 years). Linear regression models were employed to investigate the variables related to DKK-1 serum levels. ResultsIn total, 90 patients were included. Sixty-eight patients had early axSpA and 22 had established disease. Serum levels of DKK-1 were significantly higher in patients with early axSpA compared with established axSpA (22.1±12.6 vs 16.4±10.7pM; p=0.04). Among all tested variables, only symptom duration was significantly and inversely correlated with DKK-1 serum levels (beta: −0.041; p=0.01). ConclusionSerum DKK-1 levels in axSpA depend on disease duration. As disease duration increases, DKK-1 serum levels decrease. Based on this, an intensive treatment at early stages of the disease could have a better outcome on inhibiting/slowing radiographic progression in patients with axSpA.

Serum DKK-1 level in the development of ankylosing spondylitis and rheumatic arthritis: a meta-analysis.

To explore the association of serum Dickkopf-1 (DKK-1) levels with the development of ankylosing spondylitis (AS) and rheumatic arthritis (RA) in humans, databases including PubMed, EBSCO, Springerlink, Ovid, WANFANG and China National Knowledge Infrastructure (CNKI) were searched to identify relevant studies. On the basis of rigorous inclusion and exclusion criteria, case–control studies of the relationships between serum DKK-1 levels and AS and RA published before December 2014 were enrolled. Statistical analyses were performed using Comprehensive Meta-analysis 2.0 (CMA 2.0). Seven case–control trials with a total of 300 AS patients, 136 RA patients and 232 healthy controls were included in this study. Meta-analysis results revealed that DKK-1 serum levels were significantly higher in AS patients than in normal controls (standard mean differences (s.m.d.)=0.301, 95% confidence interval (CI)=0.094–0.507, P=0.004), whereas no significant difference in DKK-1 serum levels was observed between RA patients and healthy controls (s.m.d.=0.798, 95% CI=−2.166–3.763, P=0.598). Serum DKK-1 level may be closely related to the development of AS but not of RA.

Higher Level of Dickkopf-1 is Associated with Low Bone Mineral Density and Higher Prevalence of Vertebral Fractures in Patients with Ankylosing Spondylitis.

Patients with ankylosing spondylitis (AS) have an increased risk of bone loss and vertebral fractures. In this study, we explored the hypothesis that the excess bone loss and vertebral fractures might be related with the activity of the Wingless signaling pathway, and in particular with the serum levels of its circulating inhibitors, Sclerostin and Dickkopf-1 (DKK1). We recruited 71 patients diagnosed with AS. Lateral radiographs of the total spine were analyzed to detect the presence of vertebral fractures, and bone mineral density (BMD) was assessed in all patients using dual X-ray absorptiometry at lumbar spine and proximal femoral site. Blood samples were obtained and levels of C-reactive protein (CRP), DKK1, and Sclerostin were measured. Blood samples from 71 healthy sex- and age-matched volunteers were collected to be used as controls. Vertebral fractures were detected more commonly among men than in women (29 vs 8%, respectively). DKK1, but not Sclerostin serum levels, were inversely correlated to lumbar spine Z-score BMD. Patients with one or more prevalent vertebral fractures had significantly higher DKK1 levels, without significant difference in Sclerostin serum levels. A significant positive correlation was found between DKK1 serum levels and CRP (r=0.240, p=0.043). The association we found between serum DKK1 levels and BMD values and vertebral fracture prevalence suggests that DKK1 might contribute to the severity of osteoporosis in AS.

Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins.

The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50% reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25% compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.

Circulating Dickkopf-1 in hypoxic ischemic neonates

Objective: The current study aimed to determine the serum level of Dickkopf-1 (Dkk-1) in peripheral blood of neonates with hypoxic ischemic encephalopathy (HIE).Methods: We measured serum levels of Dkk-1 by ELISA in neonates with HIE (n = 20) within 24 h from symptom onset and in healthy controls (n = 20).Results: Dkk-1 serum levels increased significantly in HIE neonates than in healthy control. DKK-1 serum levels increased significantly in HIE neonates with convulsion, using multiple anti-convulsant drugs and those complicated with cranial ultrasound changes. Serum DKK-1 levels increased significantly in severe HIE patients.Conclusion: Our study provides for the first time the evidence of releasing Dkk-1 into the circulation of neonates with HIE with higher level in severe degree.