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Obstructive sleep apnea (OSA) is a prevalent, underdiagnosed disease and is considered a risk factor for cardiovascular diseases, depression, accidents, and stroke. Recent clinical practice guidelines for OSA expressed the need for a new clinical tool that establishes the Apnea–Hypopnea Index (AHI) to determine the disease burden. The serum and plasma concentrations of Osteoprotegerin (OPG), Chitinase 3-like protein 1 (YKL-40), and Cardiotrophin-1 (CT-1) in 80 subjects—52 OSA patients, 27 moderate (15 ≤ AHI ˂ 30) and 25 severe (AHI ≥ 30), and 28 non-OSA controls (AHI 0–5)—were determined. Moreover, the Total Oxidative Status (TOS), Total Antioxidative Status (TAS), and Oxidative Stress Index (OSI) were assessed in the serum and plasma to evaluate whether the severity of OSA and the concentrations of OPG, YKL-40, and CT-1 correlate with the oxidative/reductive status. The serum and plasma concentrations of YKL-40 and CT-1 were higher in the OSA group, whereas the serum and plasma concentrations of OPG were lower compared to the control group. The concentrations of OPG, YKL-40, and CT-1 in the serum and plasma correlated with AHI; however, a better correlation of the concentrations was obtained for the above-mentioned proteins in the plasma. The concentrations of YKL-40 and CT-1 in the serum and OPG in the plasma show better diagnostic capabilities for moderate and severe OSA than the concentrations of YKL-40 and CT-1 in the plasma and the concentrations of OPG in the serum. [ABSTRACT FROM AUTHOR]

Smoking can be considered a risk factor for chronic apical periodontitis (CAP). This study compared the immunoexpression of biomarkers receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), osteopontin (OPN), and tumor necrosis factor alpha (TNF-α) in CAP in smokers and nonsmokers. Twelve smokers and 12 nonsmokers diagnosed with CAP and indicated for tooth extraction were selected. Exclusion factors were teeth with a diagnosis of root fracture, previous endodontic treatment, or endoperiodontal injury, in addition to individuals with systemic diseases, under 18 years of age, users of anti-inflammatory and/or antibiotics in the last 3 months, and drug users. Specimens were processed for histopathologic and immunohistochemical analysis. Qualitative analysis of RANKL expression showed 66.66% weak/moderate and 33.33% strong in smokers and 100% weak/moderate in nonsmokers. OPG and OPN expressions were 100% negative to focal in the smoker group and 50% negative to focal and 50% weak/moderate in the nonsmoker group. TNF-α was 25% negative to focal and 75% weak/moderate in the smoker group and 33.33% negative to focal and 66.66% weak/moderate in the nonsmoker group. Quantitative analysis of the data using the Mann-Whitney U test showed that there was a significant difference in the immunoexpression of RANKL (P <.05), OPG (P <.05), and OPN (P <.05), but there was no statistical difference in the immunoexpression of TNF-α (P >.05) between the 2 groups. These findings suggest that smoking is capable of altering the inflammatory response, influencing the evolution of CAP. [ABSTRACT FROM AUTHOR]

During bone development, FasL acts not only through the traditional apoptotic mechanism regulating the amount of bone-resorbing osteoclasts, but there is also growing evidence about its effect on cell differentiation. Expression of osteoblastic factors was followed in non-differentiated and differentiating primary calvarial cells obtained from FasL-deficient (gld) mice. The gld cells showed decreased expression of the key osteoblastic molecules osteocalcin (Ocn), osteopontin (Opn), and alkaline phosphatase (Alpl) in both groups. Notably, receptor activator of nuclear factor kappa-B ligand (Rankl) was unchanged in non-differentiated gld vs. wild type (wt) cells but decreased in differentiating gld cells. Osteoprotegerin (Opg) in the gld samples was increased in both groups. Opg vs. Rankl expression levels favored Opg in the case of non-differentiated cells but Rankl in differentiating ones. These results expand information on the involvement of FasL in non-apoptotic cell pathways related to osteoblastogenesis and consequently also osteoclastogenesis and pathologies such as osteoporosis. [ABSTRACT FROM AUTHOR]

Background and Aims: Limitations of the conventional diagnostic techniques urged researchers to seek novel methods to predict, diagnose, and monitor periodontal disease. Use of the biomarkers available in oral fluids could be a revolutionary surrogate for the manual probing/diagnostic radiograph. Several salivary biomarkers have the potential to accurately discriminate periodontal health and disease. This study aimed to determine the diagnostic sensitivity and specificity of salivary interleukin (IL)‐17, receptor activator of nuclear factor‐κB ligand (RANKL), osteoprotegerin (OPG), RANKL/OPG for differentiating (1) periodontal health from disease and (2) stable and unstable periodontitis. Methods: Participants with periodontitis (n = 50) and gingivitis (n = 25), both diseases represented the cases, and subjects with healthy periodontium (n = 15) as a control were recruited for this study. Periodontitis cases were further equally subdivided into stable and unstable. Whole unstimulated salivary sample were collected from all participants. Periodontal parameters including bleeding on probing, probing pocket depth, clinical attachment loss, and number of missing teeth were recorded. The protein levels of salivary IL‐17, RANKL, and OPG were determined by using enzyme‐linked immunosorbent assays technique. Results: Salivary IL‐17, OPG, RANKL, and RANKL/OPG showed high sensitivity and specificity to differentiate periodontal health from gingivitis and periodontitis. Similar pattern was observed in discriminating stable and unstable periodontitis. Salivary IL‐17 and RANKL showed a good accuracy to differentiate gingivitis from periodontitis. However, OPG and RANKL/OPG did not exhibit enough sensitivity and specificity to differentiate the latter conditions. Conclusion: Salivary IL‐17, RANKL, OPG, and RANKL/OPG system are potential candidates for differentiating periodontal health and disease and discriminate stable and unstable periodontitis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have confirmed that bone marrow mesenchymal stem cells can increase the level of osteoprotegerin and promote bone metabolism. OBJECTIVE: To analyze the effects of bone marrow mesenchymal stem cells on bone metabolism in osteoporotic rats. METHODS: Totally 42 healthy SD rats used in the experiment were divided into sham operation group, osteoporosis group, and transplantation group (n=14 per group). Rat osteoporosis model was prepared by ovariectomized method in the osteoporosis and transplantation groups. After successful model establishment, bone marrow mesenchymal stem cells were transplanted through the tail vein. At 28 days after transplantation, the serum levels of osteoprotegerin, alkaline phosphatase, tartrate resistant acid phosphatase, osteocalcin, and insulin-like growth factor 1 were detected by ELISA. Western blot assay was used to detect FoxO1 expression in the bone tissues of rats in each group. The AG-IX biomechanics machine was utilized to detect the maximum and breaking loads of the femur. Hematoxylin-eosin staining was used to observe the bone morphology of rats. RESULTS AND CONCLUSION: (1) The expression levels of osteoprotegerin, alkaline phosphatase, and insulin-like growth factor 1 were lower in the osteoporosis group than those in the sham operation group (P < 0.05). Tartrate resistant acid phosphatase and osteocalcin expression levels were higher in the osteoporosis group than those in the sham operation group (P < 0.05). Expression levels of osteoprotegerin, alkaline phosphatase, and insulin-like growth factor 1 were higher in the transplantation group than those in the osteoporosis group (P < 0.05). Tartrate resistant acid phosphatase and osteocalcin expression levels were lower in the transplantation group than those in the osteoporosis group (P < 0.05). (2) The maximum and breaking loads were lower in the osteoporosis group than those in the sham operation group (P < 0.05). The maximum and breaking loads were higher in the transplantation group than those in the osteoporosis group (P < 0.05). (3) The trabeculae became thicker, arranged orderly, and local space was even in the transplantation group, which was significantly improved compared with the osteoporosis group. (4) The expression level of FoxO1 protein in bone marrow tissue of rats was lower in the osteoporosis group than that in the sham operation group (P < 0.05). The expression level of FoxO1 protein in bone marrow tissue of rats was higher in the transplantation group than that in the osteoporosis group (P < 0.05). (5) It is concluded that bone marrow mesenchymal stem cell transplantation can improve bone metabolism in osteoporotic rats. Its therapeutic mechanism is related to promoting the expression of osteoprotegerin, alkaline phosphatase, and FoxO1. [ABSTRACT FROM AUTHOR]

• Limited treatment options have been explored for CF related bone disease. • We demonstrated elevated RANKL, decreased OPG and elevated RANKL/OPG in people with CF relative to healthy controls. • We also show elevated RANKL/OPG in people with CF bone disease versus those without bone disease. • The RANKL/OPG difference persisted after adjusting for a number of variables known to impact bone health and may be a useful marker for low bone density in CF. • Further evaluation of the safety and efficacy of antiresorptive agents that target RANKL such as denosumab is warranted. As people with Cystic Fibrosis (CF) live longer, extra-pulmonary complications such as CF-related bone disease (CFBD) are becoming increasingly important. The etiology of CFBD is poorly understood but is likely multifactorial. Bones undergo continuous remodeling via pathways including RANK (receptor activator of NF-κB)/sRANKL (soluble ligand)/OPG (osteoprotegerin). We sought to examine the association between sRANKL (stimulant of osteoclastogenesis) and OPG levels (inhibitor of osteoclast formation) and CFBD to investigate their potential utility as biomarkers of bone turnover in people with CF. We evaluated sRANKL and OPG in plasma from people with CF and healthy controls (HC) and compared levels in those with CF to bone mineral density results. We used univariable and multivariable analysis to account for factors that may impact sRANKL and OPG. We found a higher median [IQR] sRANKL 10,896pg/mL [5,781–24,243] CF; 2,406pg.mL [659.50–5,042] HC; p = 0.0009), lower OPG 56.68pg/mL [36.28–124.70] CF; 583.20pg/mL [421.30–675.10] HC; p < 0.0001), and higher RANKL/OPG in people with CF no BD than in HC (p < 0.0001). Furthermore, we found a higher RANKL/OPG ratio 407.50pg/mL [214.40–602.60] CFBD; 177.70pg/mL [131.50–239.70] CF no BD; p = 0.007) in people with CFBD versus CF without bone disease. This difference persisted after adjusting for variables thought to impact bone health. The current screening recommendations of imaging for CFBD may miss important markers of bone turnover such as the RANKL/OPG ratio. These findings support the investigation of therapies that modulate the RANK/RANKL/OPG pathway as potential therapeutic targets for bone disease in CF. [ABSTRACT FROM AUTHOR]

Background: Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. Aims: This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. Methods: Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. Results: The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. Conclusions: Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH. [ABSTRACT FROM AUTHOR]

• Plasma osteoprotegerin levels were elevated in patients with severe/critical hemorrhagic fever with renal syndrome. • Tumor necrosis factor-α synergizes with the Hantaan virus to promote osteoprotegerin production in endothelial cells. • Plasma osteoprotegerin correlated with hemorrhagic disorder indicators of hemorrhagic fever with renal syndrome. The bleeding tendency is a hallmark of hemorrhagic fever with renal syndrome (HFRS) after Hantaan virus (HTNV) infection. Growing reports indicate the importance of osteoprotegerin (OPG) in vascular homeostasis, implying OPG might be involved in the pathogenesis of coagulopathy in patients with HFRS. Acute and convalescence plasmas of 32 patients with HFRS were collected. Enzyme-linked immunosorbent assays (ELISA) were used to detect plasma OPG levels and other parameters. The human umbilical vein endothelial cells were stimulated with HTNV and/or tumor necrosis factor-α (TNF-α) to explore the source of OPG. Plasma OPG levels of patients with HFRS were elevated and correlated positively with the severity of HFRS and negatively with platelet counts. Abundant OPG was released from endothelial cells in response to TNF-α stimuli, along with HTNV infection, which was in accordance with the findings of positive correlations between plasma OPG and TNF-α or c-reactive protein. Importantly, plasma OPG levels correlated positively with activated partial thromboplastin time and the content of d-dimer. These findings suggested that increased plasma OPG levels induced by HTNV might be an important factor for the severity of HFRS, and was likely involved in endothelium dysfunction and hemorrhagic disorder of HFRS, which might contribute to the pathogenesis of hemorrhage in HFRS. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis is an important cardiovascular disorder in beta-thalassemia major patients. The present study aimed to predict factors of atherosclerosis in children with beta-thalassemia major. Materials and Methods: This cross-sectional study was conducted on 36 patients with beta-thalassemia major and 36 healthy children as the control group. The carotid intima-media thickness (CAIMT) and osteoprotegerin (OPG) were compared between groups. Results: The mean age of the patients in the case and control groups were 13.5 ± 3.7 and 13 ± 3.1 years old, respectively. Significant differences in CAIMT in the right (P = 0.001) and left (P = 0.001) arteries were recorded between the two groups. The mean serum OPG in the beta-thalassemia group was significantly higher than the control group (3.9 ng/ml and 1.4 ng/ml, respectively, P=0.001). Conclusion: CAIMT is a non-invasive method for diagnosing atherosclerosis. According to the significant difference between groups, serum OPG could be helpful in the diagnosis of early atherosclerosis in beta-thalassemia major. [ABSTRACT FROM AUTHOR]

Soluble receptors are important for the balance between ligands and their membrane receptors. Changes in the expression of soluble receptors are associated with human diseases. The aim of this study was to determine the serum levels of sRAGE, sRANKL and OPG in subgroups of rheumatoid arthritis (RA) patients according to the level of CRP and to assess the relationship of these parameters with markers of iron and disease status. The study involved 114 RA patients. The levels of sRAGE, sRANKL and OPG were higher in the subgroup with increased CRP level compared to the subgroup with normal CRP. sRAGE showed a significant positive correlation with sTfR (r = 0.435, p < 0.0001), prohepcidin (r = 0.232, p = 0.04), sRANKL (r = 0.636, p < 0.0001), RF (r = 0.363, p < 0.002), and antiCCP antibodies (r = 0.429, p = 0.003) in the subgroup with normal CRP. Serum sRANKL was positively associated with sRAGE (r = 0.636, p < 0.0001), sTfR (r = 0.513, p < 0.0001), CRP (r = 0.223, p = 0.048), DAS28 (r = 0.269, p = 0.016), RF (r = 0.390, p = 0.001) and antiCCP antibodies (r = 0.445, p = 0.002) also in the subgroup with normal CRP. Serum OPG was positively correlated with ferritin in the subgroup with normal CRP. The association of sRAGE, sRANKL and OPG with markers of iron and disease status in RA suggests a relationship between inflammatory state, osteoclast activation and impaired iron and immune status. Therefore, sRAGE, sRANKL and OPG can be useful markers for the assessment of early pathological changes in RA and can also assist in monitoring of the therapy. [ABSTRACT FROM AUTHOR]

Objectives: Primary – a study of the correlation between serum osteoprotegerin (OPG), and biomarkers of bone metabolism in patients with treatment-naive Graves' disease (GD). Secondary – serum level of OPG, TNF-alfa, and biomarkers of bone metabolism in patients three months after treatment of GD with methimazole (MMI). Materials and Methods: A total of thirty-five treatment-naive newly diagnosed GDs were recruited for the study, most of them female. All patients started with MMI for treatment and various blood parameters were measured at baseline and three months after treatment. Measurements: Serum calcium (Ca), phosphorus (P), bone-specific alkaline phosphatase (B-ALP), OPG, TNF-alfa, and urine deoxypyridinoline (U-DPD) along with serum-free T3 and T4, thyroid-stimulating hormone (TSH) and thyroid receptor antibody (TR-ab) were analysed at baseline and three months after MMI treatment. All the patients had euthyroid at three months of MMI treatment. Results: Mean serum OPG (0.94 ± 1.39 vs. 0.63 ± 0.27 ng/ml; P = 0.262) level at baseline and after treatment with MMI did not show any significant change. Mean TSH level (0.207 ± 0.59 vs. 1.00 ± 1.95, P = 0.025) was significantly low at baseline than after treatment; FT4 (5.9 ± 5.22 v 1.77 ± 1.89 ng/dl; P < 0.001), FT3 (12.19 ± 6.91 vs. 4.99 ± 3.55 pg/ml; P < 0.001), and TNF-alfa values decreased significantly after treatment, however, PTH (58.09 ± 28.75 vs. 75.57 ± 41.50; P < 0.026) increased significantly after treatment. Discussion: There is no correlation of OPG with thyroid hormone profile, TSH, thyroid receptor antibody (TR-ab), and bone metabolic parameters such as serum Ca, P, B-ALP, TNF-alfa, and U-DPD in our study. Mean TNF-alfa decreased significantly (393.43 ± 270.473 vs. 139.34 ± 101.264 pg/ml; P = 0.001) level after treatment with MMI. TNF-alfa was positively correlated with TR-ab (r = 0.374; P = 0.027) and B-ALP (r = 0.388; P = 0.021). Conclusion: The bone turnover marker in GD seems to be mediated other than OPG. We observed an increase in circulating TNF-alfa in GD with a significant decrease after treatment. TNF-alfa could be a marker of GD activity as evidenced by a close positive correlation with TR-ab, a sensitive marker of GD autoimmunity. TNF-alfa could be a factor associated with bone turnover markers in GD despite its euthyroid state. [ABSTRACT FROM AUTHOR]

Periodontitis is a disease that damages the periodontal tissue and can cause tooth loss. In recent years there has been an interest in carrying out regenerative efforts as periodontal therapy. Bonegraft derived from natural materials is the current choice because of the limitations of the available synthetic bonegrafts. The aim of this study was to analyze the effect of golden sea cucumber on the increase of BMP2 and Osteoprotegrin on bone regeneration. This research is a laboratory experimental study with male guinea pigs as the subject. The number of samples is 30 guinea pigs. After 14 and 21 days sacrificed was performed for immunohistochemical examination. The expression of BMP2 and OPG had a significant difference between the sea cucumber group and the positive control group. It can be concluded that bonegraft from golden sea cucumbers has a mechanism as bonegraft material so that it can be used as an alternative material in regenerative therapy. [ABSTRACT FROM AUTHOR]

Platelets play an essential role in wound healing and periodontal regeneration, so using platelet concentrates can speed up wound healing after periodontal treatment. Platelet-rich fibrin (PRF), an autogenous concentrated blood product, is a fibrin matrix comprising molecular and cellular elements that allow for optimum improvement and PRF also increases the production of osteoprotegerin, which causes osteoblast proliferation and acts as an osteoconductive and osteoinductive material, initiating bone regeneration. Platelet-rich plasma (PRP) and PRF are platelet concentrates prepared from the patient's own blood. Recent studies have focused on the development of therapeutic alternatives that are simple to prepare, non-toxic or biocompatible to living tissues, and inexpensive, with the potential to result in the local release of growth factors that accelerate hard and soft tissue healing. PRP is a plasma fraction that contains a high concentration of growth factors. PRF is a natural fibrin-based biomaterial derived from an anticoagulant-free blood harvest without any artificial biochemical modification, allowing fibrin membranes enriched with platelets and growth factors to be obtained. It facilitates the application of growth factors to the surgical area in a concentrated form, thereby accelerating wound improvement and regeneration. Platelet concentrates are used in many areas of dentistry, including soft tissue improvement, plastic periodontal surgery, gingival enlargement, ridge preservation, regeneration of bone defects, drug-related osteonecrosis of the jawbone, sinus augmentation, immediate implant placement, and implant osseointegration. Their use is preferred due to their ease of application and low cost. This paper reviews the current literature concerning the utilization of platelet-rich fibrin in periodontology. [ABSTRACT FROM AUTHOR]

Colorectal carcinoma (CRC) is one of the most prevalent forms of malignant tumors worldwide, with over 600,000 CRC-related deaths occurring annually. Despite major advances in surgical techniques and equipment, chemotherapy and radiation therapy, the prognosis for CRC patients remains poor because of distant metastasis and recurrence. Traditionally, the identification of patients at high risk of recurrence or distant metastasis has depended on pathological characteristics, such as depth of invasion, nodal metastasis, stage group and perforation or invasion of adjacent organs. However, the current tumor-node-metastasis (TNM) classification system is limited in that it cannot offer a prognosis for individual patients. To improve the outcome of patients with CRC, it is crucial to identify cancer-related genes that can serve as predictive and prognostic biomarkers to individualize therapy. Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor superfamily. It has been shown that OPG is involved in the development and progression of human malignancies. This review summarizes our current understanding of the role of OPG in fibrosis and will discuss its potential as a biomarker and/or novel therapeutic target for fibrosis. [ABSTRACT FROM AUTHOR]

Osteoblasts produce the receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin, the inducer and the suppressor of osteoclast differentiation and activation. We previously proposed that the degradation of osteoprotegerin by lysine-specific gingipain of Porphyromonas gingivalis and neutrophil elastase is one of the mechanisms of bone resorption associated with infection and inflammation. In the present study, we found that cathepsin K (CTSK) also degraded osteoprotegerin in an acidic milieu and the buffer with a pH of 7.4. The 37 k fragment of osteoprotegerin produced by the reaction with CTSK was further degraded into low molecular weight fragments, including a 13 k fragment, depending on the reaction time. The N-terminal amino acid sequence of the 37 k fragment matched that of the intact osteoprotegerin, indicating that CTSK preferentially hydrolyzes the death domain-like region of osteoprotegerin, not its RANKL-binding region. The 13 k fragment of osteoprotegerin was the C-terminal 13 k portion within the RANKL-binding region of the 37 k fragment. Finally, CTSK restored RANKL-dependent osteoclast differentiation that was suppressed by the addition of osteoprotegerin. Collectively, CTSK is a possible positive regulator of osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Objectives: Peri-implantitis was an inflammatory progress on the tissue around the implant. The Osteoprotegerin G1181C (rs2073618) polymorphism was reported to be related to the increased risk of the peri-implantitis, whereas another found no relationship. The present study was conducted to research the relationship between Osteoprotegerin rs2073618 polymorphism and peri-implantitis susceptibility. Materials and methods: The meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews. Electronic databases including PubMed, Web of science, Springer Link and Embase (updated to April 15, 2022) were retrieved. The cohort study, case-control study or cross-sectional study focusing on the Osteoprotegerin rs2073618 polymorphism and peri-implantitis were retrieved. The data included basic information of each study and the genotype and allele frequencies of the cases and controls. Results: Three studies were finally included, including 160 cases and 271 controls. Allelic model, homozygote model, recessive model, dominant model, and heterozygous model were established to assess the relationship between OPG rs2073618 polymorphism and peri-implantitis susceptibility. The Osteoprotegerin rs2073618 polymorphism was significantly associated with peri-implantitis in Recessive model and Homozygote model. Conclusion: OPG rs2073618 polymorphism in Recessive model and Homozygote model was highly likely related to the risk of peri-implantitis. PROSPERO registration number: CRD42022320812 [ABSTRACT FROM AUTHOR]

Introduction: For the past years, the prevalence of obesity is growing in the general population of children, as well as among diabetic patients, resulting in increased risk of cardiovascular complications. Type 1 diabetes mellitus (T1DM) is one of the most common chronic sdiseases in children and young adults, leading to decreased life quality and lifespan, with obesity being recognized recently as a major contributing factor to these health problems. The objective of this study was to analyze and compare the selected novel markers for metabolic complications of obesity and vascular risk factors between obese non-diabetic and obese T1DM children and young adults. Methods: One hundred four subjects, aged between 10 and 24 years (31 with T1DM and excessive body weight, 41 with obesity without diabetes, and 32 with T1DM and normal weight), and 32 matched lean controls were included in the study. Clinical characteristics, blood pressure measurements, daily requirement for insulin, HbA1c%, plasma lipids, fetuin-A, E-selectin, and osteoprotegerin levels were compared with respect to body mass index (BMI), body mass index standard deviation score (BMI-SDS), and carotid intima-media thickness (cIMT) of common carotid arteries. Results: Patients with T1DM and excessive body weight compared to non-diabetic obese subjects had similar values of systolic blood pressure (125.6 ± 8.2 vs. 127.3 ± 12.9 mmHg, p = 0.515), diastolic blood pressure (78.19 ± 7.03 vs. 78.02 ± 8.01 mmHg, p = 0.918), cholesterol (175.26 ± 34.1 vs. 163.51 ± 26.08 mg/dl, p = 0.102), LDL (108.03 ± 32.55 vs. 112.22 ± 26.36 mg/dl, p = 0.548), and triglyceride levels (118.19 ± 71.20 vs. 117 ± 55.80 mg/dl, p = 0.937); all values were found to be higher compared to non-obese T1DM and healthy controls. HbA1c level and insulin resistance indices were significantly worse in T1DM obese vs. T1DM non-obese patients. Fetuin-A levels were higher among obese non-diabetic patients (p = 0.01), and E-selectin and osteoprotegerin levels were similar in both groups with obesity, but higher than in the reference group. There were no statistical differences in cIMT with T1DM with normal weight, excessive weight, and non-diabetic obese children; however, the cIMT value was higher compared to the reference group. Discussion: Novel markers of metabolic complications of obesity are similar between obese T1DM and non-diabetic subjects. Obesity in patients with T1DM results in worse metabolic control, insulin resistance, and increased risk for vascular complications. [ABSTRACT FROM AUTHOR]

Objective To observe the expression of serum osteoprotegerin (OPG) and soluble receptor activator of nuclear factor κB ligand (sRANKL) levels in patients with chronic heart failure (CHF), and to explore the relationship between those and osteoporosis in CHF patients, providing value for the diagnose and intervention of CHF patients with osteoporosis. Methods CHF patients hospitalized from January 2020 to August 2021 were selected to detect serum OPG and sRANKL and bone mineral density (BMD) levels. They were divided into non-osteoporosis group and osteoporosis group according to bone mass. The serum OPG and sRANKL levels and their correlation with bone mineral density were compared between the two groups. The diagnostic value of OPG and sRANKL levels in CHF patients with osteoporosis was analyzed. Results (1) Serum levels of OPG and sRANKL in CHF patients with osteoporosis were higher than those in CHF patients without osteoporosis, and the differences were statistically significant (P<0. 00 1). (2) Serum OPG and sRANKL levels were negatively correlated with BMD in CHF patients (r = -0. 595/-0. 458, P<0. 001). (3) Serum OPG and sRANKL were risk factors for osteoporosis in CHF patients (OR= 1. 004, P = 0. 005; OR= 1. 061, P = 0. 011). (4) ROC curve was used to analyze the predictive value of serum OPG and sRANKL levels on osteoporosis in CHF patients. The area under ROC curve (AUC) was 0. 761 and 0. 703, respectively (P<0. 001). When OPG = 246. 93, the highest Youden index was 0. 431, which had the greatest diagnostic value for osteoporosis in CHF. The sensitivity and specificity were 0. 769 and 0. 662, respectively. When sRANKL = 20. 275, the Y ouden index was 0. 385, and the sensitivity and specificity were 0. 635 and 0. 750, respectively, which had the greatest diagnosis value for osteoporosis in CHF. Conclusion Monitoring serum OPG and sRANKL levels may be helpful to detect osteoporosis in patients with CHF, providing an important reference for clinical diagnosis and treatment of CHF combined with osteoporosis. [ABSTRACT FROM AUTHOR]

The development of targeted therapy such as tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-based therapy has gained increasing attention as a promising new approach in cancer therapy. TRAIL specifically targets cancer cells while sparing the normal cells, thus, limiting the known side effects of the majority anti-cancer therapies. As more extensive research and clinical trials are conducted, resistance to TRAIL molecule has become one of the significant issues associated with the failure of TRAIL in treating colorectal cancer (CRC). To date, the exact mechanism by which TRAIL resistance may have occurred remains unknown. Interestingly, recent studies have revealed the critical role of the TRAIL decoy receptor family; consisting of decoy receptor 1 (DcR1; also known as TRAIL-R3), decoy receptor 2 (DcR2; also known as TRAIL-R4), and osteoprotegerin (OPG) in driving TRAIL resistance. This review highlights the expression of the decoy receptors in CRC and its possible association with the reduction in sensitivity towards TRAIL treatment based on the currently available in vitro, in vivo, and human studies. Additionally, discrepancies between the outcomes from different research groups are discussed, and essential areas are highlighted for future investigation of the roles of decoy receptors in modulating TRAIL-induced apoptosis. Overcoming TRAIL resistance through modulating the expression(s) and elucidating the role(s) of TRAIL decoy receptors hold great promise for TRAIL-based therapies to be extensively explored in treating human cancers including CRC. [ABSTRACT FROM AUTHOR]

Our current results also found that OPG levels were significantly lower in the group with massive albuminuria than in the group without albuminuria, according to albuminuria and eGFR categories, and OPG levels were not associated with the degree of renal impairment. However, in the massive albuminuria group, OPG expression can be positive in the renal tubules, and it is significantly higher than that in the microalbuminuria group.[8] This may be one of the reasons supporting a more significant relationship between OPG and massive albuminuria. [Extracted from the article]

Objective The expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) in human periodontal ligament cells (HPDLCs) was investigated by cell culture under continuous static pressure. Methods HPDLCs were primarily cultured by tissue explant method and divided into three groups: group A (13-18 years old), group B (19-29 years old), and group C (30-44 years old). CCK-8 was used to detect the proliferation of HPDLCs. The senescence of HPDLCs was detected by senescence-associated β-galactosidase staining. Cells in the three groups were respectively given 0, 1.5, 3, 6, 12, 24, 48, and 72 h of continuous static pressure in vitro. The expression of OPG and RANKL in the supernatant was detected by enzyme-linked immunosorbent assay. Results After continuous static pressure in vitro for stimulation, the expression of OPG and RANKL changed. The expression of OPG increased with time and age (P<0.01). The expression of RANKL increased with time and decreased with age (P<0.01). The ratio of OPG/RANKL initially decreased, increased with time, and then continued to rise with age (P<0.01). Conclusion Aging could increase the expression of OPG and the ratio of OPG/RANKL and decrease the expression of RANKL in HPDLCs under continuous static pressure in vitro. [ABSTRACT FROM AUTHOR]

Abstract Background Bone-related proteins (such as sclerostin and osteoprotegerin [OPG]) are involved in the development of atherosclerosis. However, the relationship between bone-related proteins and acute myocardial infarction (AMI) has not been extensively evaluated. The purpose of this study was to assess the association of serum sclerostin and OPG with the presence, severity and prognosis in patients with AMI. Methods This study prospectively enrolled 152 patients attacked by acute chest pain. Serum sclerostin and OPG were detected within the first 24 h after AMI diagnosis by ELISA kits. The AMI predictive efficacy of sclerostin and OPG were analyzed by receiver operating characteristics (ROC) curve. Univariable and multivariable linear regression analyses were performed to determine the association between bone-related proteins and scores indicating the severity of coronary artery occlusion. Moreover, prognostic values were assessed by Kaplan–Meier curves and Cox regression analysis. Results There were 92 patients in AMI group, 60 in non-AMI group. Serum levels of sclerostin and OPG were significantly higher in AMI group than in non-AMI group (all p

Abstract Women with a pathogenic germline mutation in the BRCA1 gene face a very high lifetime risk of developing breast cancer, estimated at 72% by age 80. Prophylactic bilateral mastectomy is the only effective way to lower their risk; however, most women with a mutation opt for intensive screening with annual MRI and mammography. Given that the BRCA1 gene was identified over 20 years ago, there is a need to identify a novel non-surgical approach to hereditary breast cancer prevention. Here, we provide a review of the emerging preclinical and epidemiologic evidence implicating the dysregulation of progesterone-mediated receptor activator of nuclear factor κB (RANK) signaling in the pathogenesis of BRCA1-associated breast cancer. Experimental studies have demonstrated that RANK inhibition suppresses Brca1-mammary tumorigenesis, suggesting a potential target for prevention. Data from studies conducted among women with a BRCA1 mutation further support this pathway in BRCA1-associated breast cancer development. Progesterone-containing (but not estrogen-alone) hormone replacement therapy is associated with an increased risk of breast cancer in women with a BRCA1 mutation. Furthermore, BRCA1 mutation carriers have significantly lower levels of circulating osteoprotegerin (OPG), the decoy receptor for RANK-ligand (RANKL) and thus endogenous inhibitor of RANK signaling. OPG levels may be associated with the risk of disease, suggesting a role of this protein as a potential biomarker of breast cancer risk. This may improve upon current risk prediction models, stratifying women at the highest risk of developing the disease, and further identify those who may be targets for anti-RANKL chemoprevention. Collectively, the evidence supports therapeutic inhibition of the RANK pathway for the primary prevention of BRCA1-associated breast cancer, which may generate unique prevention strategies (without prophylactic surgery) and enhance quality of life.

Background Osteoprotegerin is an important regulator of bone metabolism and vascular calcification. The association between serum osteoprotegerin level and chronic kidney disease (CKD) progression has not been elucidated. We investigated the prognostic value of serum osteoprotegerin levels in nondialysis CKD patients. Methods We analyzed 2,082 patients enrolled in the Korean Cohort Study for Outcomes in Patients with CKD between 2011 and 2016. Patients were divided into quartiles by their serum osteoprotegerin levels. The primary outcome was the occurrence of ≥1 of the following: dialysis initiation, kidney transplantation, a two-fold increase in serum creatinine level from baseline, or a 50% decrease in the estimated glomerular filtration rate (eGFR). Cox proportional hazard regression models were used to investigate the prognostic value of the serum osteoprotegerin level to CKD progression. Results The median follow-up period was 48.9 months, and 641 patients (30.8%) experienced the primary outcome. The hazard ratio of serum osteoprotegerin for renal progression in the full extended Cox proportional hazard model was 1.064 (95% confidence interval, 1.041–1.088). Subgroup analyses by age, presence of diabetes, and eGFR showed significant results consistent with the overall analysis results. Conclusion Serum osteoprotegerin level is independently associated with renal prognosis and could have prognostic importance in CKD progression.

The use of nanotechnology and polymer-based carriers in osteoporosis treatment offers promising avenues for targeted drug delivery and enhanced therapeutic efficacy. In this study, we developed a novel nanoconjugate composed of Chitosan (CH), Chondroitin Sulfate (CS), and Daidzein (DZ) to treat glucocorticoid-induced osteoporosis in an in vivo zebrafish model. The CH-CS-DZ nanoconjugate were synthesized using the ionic gelation method, with a CH: CS ratio of 1:1 and a 3 % DZ concentration was identified as optimal for further analysis. The resulting nanoparticles exhibited a particle size of 401.2 ± 0.87 nm. The polydispersity index (PDI) and zeta potential of nanoconjugate were of 0.147 ± 0.04 and 43.55 ± 0.68 mV respectively. Drug release studies demonstrated that 79.66 ± 4.04 % of DZ was released under physiological conditions (pH 7.5) after 96 h, indicating a sustained release profile beneficial for prolonged therapeutic effects. In vivo , studies using zebrafish larvae revealed a significant reduction in oxidative stress and apoptosis in the CH-CS-DZ treated group compared to the glucorticoid dexamethasone (Dex) treated group. Specifically, reactive oxygen species (ROS) levels were reduced, and lipid peroxidation was markedly decreased (p < 0.001) in the CH-CS-DZ treated group. Additionally, the survival and hatching rates of CH-CS-DZ-treated larvae were 94 % and 95 %, respectively, significantly higher than those in the Dex-treated group. The CH-CS-DZ nanoconjugate also restored bone mineralization, as evidenced by a significant increase in calcium deposition (p < 0.001) and alkaline phosphatase (ALP) activity (122 ± 0.4 U/L), compared to the Dex group (84 ± 0.7 U/L). Gene expression analysis showed upregulation of OPG and ALP and downregulation of RANKL and RUNX2b, further indicating the anti-osteoporotic potential of the CH-CS-DZ nanoconjugates. These findings suggest that polymer-based nanoconjugates like CH-CS-DZ can effectively mitigate osteoporosis through targeted delivery and sustained release, offering a potent strategy for bone health restoration. [ABSTRACT FROM AUTHOR]

Gallein is a known Gβγ subunit inhibitor, but its function in bone metabolism, especially in osteoblasts, and its molecular mechanism remains to be elucidated. Osteoprotegerin (OPG), which is secreted from osteoblasts, binds to nuclear factor kB receptor activator (RANK) ligand (RANKL) as a decoy receptor, prevents RANKL-RANK binding, and inhibits bone resorption. IL-6 is not only a bone resorption factor but also as a bone metabolism regulator. Prostaglandin F2α (PGF2α) promotes p44/p42 MAPK, p38 MAPK and stress-activated protein kinase/JNK phosphorylation in osteoblast-like MC3T3-E1 cells. In MC3T3-E1 cells, activated p44/p42 and p38 MAPKs promote IL-6 secretion and activated p44/p42 and p38 MAPKs and JNK promote OPG secretion. The present study aimed to investigate the effect and mechanism of gallein on PGF2α-induced OPG and IL-6 secretion using an osteoblastic MC3T3-E1 cell line. It was found that gallein significantly increased PGF2α-induced OPG and IL-6 secretion in the MC3T3-E1 cell. By contrast, fluorescein, which is a gallein-like compound that does not bind to Gβγ, did not affect PGF2α-induced OPG and IL-6 secretion. Gallein significantly improved the PGF2α-induced OPG and IL-6 mRNA expression levels. Gallein did not affect the PGF2α-activated phosphorylation of p44/p42 and p38 MAPKs and JNK. Gallein increased PGF2α-induced OPG and IL-6 secretion in osteoblasts, indicating that gallein may regulate bone remodeling via OPG/IL-6 in bone metabolism. [ABSTRACT FROM AUTHOR]

Background and Objectives: Osteoprotegerin (OPG), a soluble glycoprotein found in serum, has been associated with both the presence and severity of atherosclerosis. OPG is regarded as the mediator in the process of vascular endothelial dysfunction. Impaired endothelial function has an intimate link with hypertension (HTN) and is associated with significant morbidity and mortality. This study was to investigate the connection between OPG and endothelial dysfunction in patients having HTN. Materials and Methods: There are 102 patients with HTN included. For the purpose of determining the levels of OPG, a commercial enzyme-linked immunosorbent test kit was applied. The vascular reactivity index (VRI), which is assessed via the digital thermal monitoring, provides information on endothelial function. Results: Ten patients with HTN (9.8%) were classified as having poor vascular reactivity (VRI < 1.0), 46 HTN patients (45.1%) as having intermediate vascular reactivity (1.0 ≤ VRI < 2.0), and 46 HTN patients (45.1%) were classified as having high vascular reactivity (VRI ≥ 2.0). A greater serum OPG level (p < 0.001) and older age (p = 0.022) were linked to impaired vascular reactivity. The estimated glomerular filtration rate (r = 0.196, p = 0.048) was positively correlated with VRI values in hypertensive participants, while advanced age (r = −0.222, p = 0.025) and the log-transformed OPG level (log-OPG, r = −0.357, p < 0.001) were negatively correlated with VRI. Serum log-OPG level was shown to be strongly and independently correlated with VRI values in HTN individuals after multivariable forward stepwise linear regression analysis (β = −0.357, adjusted R2 change = 0.119, p < 0.001). Conclusions: In patients with HTN, serum OPG levels were adversely correlated with VRI and probably had a role in endothelial dysfunction.

Background: The process of tooth eruption is influenced by local, systemic, and genetic factors. Any disturbances in these factors might lead to abnormalities in the eruption of the tooth. Aim: The aim of this narrative review is to classify and discuss the eruption and its abnormality in detail. Methods: This narrative review was performed through an electronic search of data for the articles dealing with eruption, theories of eruption, and eruption abnormalities from the following databases such as PubMed, Scopus, Medknow, WebMD, and IndMed. Results: Based on our search, we were able to retrieve the information from 15 articles. Conclusion: A mastered eye in evaluating the radiographs, the practitioner's acquaintance with associated abnormalities, and the patient's clear history including familial and traumatic history might pave the way in arriving at an approximate diagnosis.

Paul T Williams Molecular Biophysics & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USACorrespondence: Paul T Williams Email ptwilliams@lbl.govPurpose: Heritability (h2, the proportion of the phenotypic variance attributable to additive genetic effects) is traditionally assumed to be constant throughout the distribution of the phenotype. However, the heritabilities of circulating C-reactive protein, interleukin-6, plasminogen activator inhibitor type-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) concentrations depend upon whether the phenotype is high or low relative to their distributions (quantile-dependent expressivity), which may account for apparent gene–environment interactions. Whether the heritabilities of other inflammatory biomarkers linked to cardiovascular disease are quantile-dependent remain to be determined.Patients and Methods: Quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted phenotypes of families surveyed as part of the Framingham Heart Study. Quantile-specific heritabilities were calculated as: h2=2βOP/(1+rspouse) and h2={(1+8rspouseβFS)0.5– 1}/(2rspouse).Results: Heritability (h2 ± SE) of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass concentrations increased from 0.11 ± 0.03 at the 10th percentile, 0.08 ± 0.03 at the 25th, 0.12 ± 0.03 at the 50th, 0.20 ± 0.04 at the 75th, and 0.26 ± 0.06 at the 90th percentile, or 0.0023 ± 0.0006 per each one-percent increase in the phenotype distribution (Plinear trend= 0.0004). Similarly, h2 increased 0.0029 ± 0.0011 (Plinear trend= 0.01) for sP-selectin, 0.0032 ± 0.0009 (Plinear trend= 0.0001) for soluble intercellular adhesion molecule 1 (sICAM-1), and 0.0026 ± 0.0006 for tumor necrosis factor receptor 2 (TNFR2) (Plinear trend= 5.0 × 10− 6) per each one-percent increase in their distributions when estimated from βOP. Osteoprotegerin and soluble ST2 heritability also increased significantly with increasing percentiles of their distributions when estimated from βFS. Lp-PLA2 activity, CD40 ligand, TNFα, interleukin-18, and myeloperoxidase heritability showed no significant quantile-dependence.Conclusion: The heritabilities of circulating Lp-PLA2-mass, sP-selectin, sICAM-1, TNFR2, osteoprotegerin and soluble ST2 concentrations are quantile-dependent, which may contribute to purported genetic modulations of: 1) sP-selectin’s relationships to venous thrombosis, pulmonary hypertension, type 2 diabetes and atorvastatin treatment; 2) sICAM-I’s relationships to brain abscess and atorvastatin treatment; and 3) Lp-PLA2’s relationships to myocardial infarction and preeclampsia.Keywords: gene–environment interaction: heritability, P-selectin, intercellular adhesion molecule-1, lipoprotein-associated phospholipase A2, osteoprotegerin

Resumen: Objetivo: El alcance de este estudio fue evaluar los niveles de osteoprotegerina (OPG) salival y sérica en la osteoartritis de rodilla (OA). Métodos: Los niveles de OPG en suero y saliva de 30 OA y 30 controles sanos emparejados en este estudio transversal se evaluaron mediante ELISA. El dolor de rodilla fue evaluado por The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Los datos se analizaron mediante la prueba t de Student, la prueba de correlación de Spearman y receiver operating characteristic (ROC). Resultados: El nivel medio de OPG en suero, pero no en saliva fue menor en la artrosis de rodilla que en el grupo sano. WOMAC se correlacionó negativamente con la OPG sérica (r = −0,501; p = 0,000). El valor de corte de OPG sérico fue de 237,5 pg/mL para el diagnóstico de OA de rodilla. Conclusiones: Como la OPG sérica fue más baja en la artrosis de rodilla y se correlacionó negativamente con WOMAC, parece que la detección de OPG en suero, pero no en la saliva puede ser un marcador probable para el diagnóstico de artrosis de rodilla. Mensajes clave: La osteoprotegerina disminuye en la osteoartritis de rodilla. Abstract: Objective: The scope of this study was to assess salivary and serum osteoprotegerin (OPG) levels in knee osteoarthritis (OA). Methods: Serum and saliva OPG levels of 30 knee OA and 30 matched healthy controls in this cross-sectional study was assessed by ELISA. Knee pain was assessed by WOMAC. Data were analyzed by Student's t-test, Spearman correlation test and ROC. Results: The mean serum but not saliva OPG level was lower in knee OA than that of the healthy group. WOMAC negatively correlated with serum OPG (r = −0.501; P = 0.000). The serum OPG cutoff value was 237.5 pg/ml for the diagnosis of knee OA. Conclusions: As serum OPG was lower in knee OA and negatively correlated with WOMAC, it seems that detection of OPG in serum but not in saliva may be a probable marker to the diagnosis of knee OA. Key messages: Osteoprotegerin decreases in knee osteoarthritis.

Abstract Background and Aims Limitations of the conventional diagnostic techniques urged researchers to seek novel methods to predict, diagnose, and monitor periodontal disease. Use of the biomarkers available in oral fluids could be a revolutionary surrogate for the manual probing/diagnostic radiograph. Several salivary biomarkers have the potential to accurately discriminate periodontal health and disease. This study aimed to determine the diagnostic sensitivity and specificity of salivary interleukin (IL)‐17, receptor activator of nuclear factor‐κB ligand (RANKL), osteoprotegerin (OPG), RANKL/OPG for differentiating (1) periodontal health from disease and (2) stable and unstable periodontitis. Methods Participants with periodontitis (n = 50) and gingivitis (n = 25), both diseases represented the cases, and subjects with healthy periodontium (n = 15) as a control were recruited for this study. Periodontitis cases were further equally subdivided into stable and unstable. Whole unstimulated salivary sample were collected from all participants. Periodontal parameters including bleeding on probing, probing pocket depth, clinical attachment loss, and number of missing teeth were recorded. The protein levels of salivary IL‐17, RANKL, and OPG were determined by using enzyme‐linked immunosorbent assays technique. Results Salivary IL‐17, OPG, RANKL, and RANKL/OPG showed high sensitivity and specificity to differentiate periodontal health from gingivitis and periodontitis. Similar pattern was observed in discriminating stable and unstable periodontitis. Salivary IL‐17 and RANKL showed a good accuracy to differentiate gingivitis from periodontitis. However, OPG and RANKL/OPG did not exhibit enough sensitivity and specificity to differentiate the latter conditions. Conclusion Salivary IL‐17, RANKL, OPG, and RANKL/OPG system are potential candidates for differentiating periodontal health and disease and discriminate stable and unstable periodontitis.

Calcium phosphate (CaP) is the inorganic part of hard tissues, such as bone, teeth and tendons, and has a high biocompatibility and good biodegradability. Therefore, CaP nanoparticles functionalized with DNA encoding bone anabolic factors are promising carrier-systems for future therapeutic development. Here, we analysed CaP nanoparticles in a genetically modified medaka fish model, where osteoporosis-like lesions can be induced by transgenic expression of receptor activator of nuclear factor kappa-B ligand (Rankl). Rankl-transgenic medaka were used to visualize and understand effects of microinjected functionalized CaP nanoparticles during modulation of osteoclast activity in vivo. For this, we synthetized multi-shell CaP nanoparticles by rapid precipitation of calcium lactate and ammonium hydrogen phosphate followed by the addition of plasmid DNA encoding the osteoclastogenesis inhibitory factor osteoprotegerin-b (Opgb). An additional layer of poly(ethyleneimine) was added to enhance cellular uptake. Integrity of the synthesized nanoparticles was confirmed by dynamic light scattering, scanning electron microscopy and energy dispersive X-ray spectroscopy. Fluorescently labelled CaP nanoparticles were microinjected into the heart, trunk muscle or caudal fins of Rankl-transgenic medaka embryos that expressed fluorescent reporters in various bone cell types. Confocal time-lapse imaging revealed a uniform distribution of CaP nanoparticles in injected tissues and showed that nanoparticles were efficiently taken up by macrophages that subsequently differentiated into bone-resorbing osteoclasts. After Rankl induction, fish injected with Opg-functionalized nanoparticles showed delayed or absent degradation of mineralized matrix, i.e. a lower incidence of osteoporosis-like phenotypes. This is proof of principle that CaP nanoparticles can be used as carriers to efficiently deliver modulatory compounds to osteoclasts and block their activity.

Background Angiotensin II type 1 receptor blockers (ARBs) have been shown to limit the growth of abdominal aortic aneurysm (AAA), but their efficacy is controversial. This study aimed to investigate the molecular mechanism underlying the protective effect of ARBs against AAA progression. Methods and Results Olmesartan, an ARB, was administered to wild‐type and osteoprotegerin‐knockout (Opg‐KO) mice starting 2 weeks before direct application of CaCl2 to aortas to induce AAA. The protective effect of olmesartan against AAA in wild‐type and Opg‐KO mice was compared at 6 weeks after AAA induction. Olmesartan prevented AAA progression in Opg‐KO mice, including excessive aortic dilatation and collapse of tunica media, but not in wild‐type mice. Deficiency of the Opg gene is known to cause excessive activation of the tumor necrosis factor–related apoptosis‐inducing ligand–induced c‐Jun N‐terminal kinase/matrix metalloproteinase 9 pathway, resulting in prolonged AAA progression. Olmesartan attenuated the upregulation of phosphorylated c‐Jun N‐terminal kinase and matrix metalloproteinase 9 expression in the aortic wall of Opg‐KO mice. In cultured vascular smooth muscle cells, tumor necrosis factor–related apoptosis‐inducing ligand–induced c‐Jun N‐terminal kinase phosphorylation and matrix metalloproteinase 9 expression were inhibited by angiotensin (1–7), the circulating levels of which are increased by ARBs. Furthermore, administering an angiotensin (1–7) antagonist to Opg‐KO mice diminished the protective effect of olmesartan against AAA progression. Conclusions Olmesartan prevented AAA progression in Opg‐KO mice by upregulating angiotensin (1–7), suggesting that angiotensin (1–7) may be a key factor that mediates the protective effect of ARBs.

BackgroundThe contributions of the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) axis to cardiovascular and bone disease in treated HIV-1 infection are not well defined.SettingProspective, observational, longitudinal study.MethodsIn a subset analysis of a prospective randomized clinical trial, 234 HIV-1-infected antiretroviral therapy-naive participants received tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir and achieved plasma HIV-1 RNA

Background Dickkopf-1 (DKK1) regulates bone formation by inhibiting canonical Wnt/β-catenin pathway signaling, and indirectly enhances osteoclastic activity by altering the expression ratio of receptor activator of nuclear factor-κB ligand (RANKL) relative to osteoprotegerin (OPG). However, it is difficult to explain continued bone loss after allogeneic stem cell transplantation (allo-SCT) in terms of changes in only RANKL and OPG. Few studies have evaluated changes in DKK1 after allo-SCT. Methods We prospectively enrolled 36 patients with hematologic malignancies who were scheduled for allo-SCT treatment. Serum DKK1, OPG, and RANKL levels were measured before (baseline), and at 1, 4, 12, 24, and 48 weeks after allo-SCT treatment. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry before (baseline) and 24 and 48 weeks after allo-SCT treatment. Results After allo-SCT treatment, the DKK1 level decreased rapidly, returned to baseline during the first 4 weeks, and remained elevated for 48 weeks (P

IntroductionFor the past years, the prevalence of obesity is growing in the general population of children, as well as among diabetic patients, resulting in increased risk of cardiovascular complications. Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in children and young adults, leading to decreased life quality and lifespan, with obesity being recognized recently as a major contributing factor to these health problems. The objective of this study was to analyze and compare the selected novel markers for metabolic complications of obesity and vascular risk factors between obese non-diabetic and obese T1DM children and young adults.MethodsOne hundred four subjects, aged between 10 and 24 years (31 with T1DM and excessive body weight, 41 with obesity without diabetes, and 32 with T1DM and normal weight), and 32 matched lean controls were included in the study. Clinical characteristics, blood pressure measurements, daily requirement for insulin, HbA1c%, plasma lipids, fetuin-A, E-selectin, and osteoprotegerin levels were compared with respect to body mass index (BMI), body mass index standard deviation score (BMI-SDS), and carotid intima-media thickness (cIMT) of common carotid arteries.ResultsPatients with T1DM and excessive body weight compared to non-diabetic obese subjects had similar values of systolic blood pressure (125.6 ± 8.2 vs. 127.3 ± 12.9 mmHg, p = 0.515), diastolic blood pressure (78.19 ± 7.03 vs. 78.02 ± 8.01 mmHg, p = 0.918), cholesterol (175.26 ± 34.1 vs. 163.51 ± 26.08 mg/dl, p = 0.102), LDL (108.03 ± 32.55 vs. 112.22 ± 26.36 mg/dl, p = 0.548), and triglyceride levels (118.19 ± 71.20 vs. 117 ± 55.80 mg/dl, p = 0.937); all values were found to be higher compared to non-obese T1DM and healthy controls. HbA1c level and insulin resistance indices were significantly worse in T1DM obese vs. T1DM non-obese patients. Fetuin-A levels were higher among obese non-diabetic patients (p = 0.01), and E-selectin and osteoprotegerin levels were similar in both groups with obesity, but higher than in the reference group. There were no statistical differences in cIMT with T1DM with normal weight, excessive weight, and non-diabetic obese children; however, the cIMT value was higher compared to the reference group.DiscussionNovel markers of metabolic complications of obesity are similar between obese T1DM and non-diabetic subjects. Obesity in patients with T1DM results in worse metabolic control, insulin resistance, and increased risk for vascular complications.

Purpose: This study examined osteokines related to Wnt signaling at rest and in response to plyometric exercise in 12 boys [10.2 (0.4) y] and 12 girls [10.5 (0.4) y]. Methods: One resting (preexercise) and 3 postexercise (5 min, 1 h, and 24 h) blood samples were analyzed for sclerostin, dickkopf-related protein 1 (DKK-1), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-β ligand (RANKL). Results: Girls had higher resting sclerostin than boys [187.1 (40.1) vs 150.4 (36.4) pg·mL−1, respectively; P =.02]. However, boys had higher DKK-1 [427.7 (142.3) vs 292.8 (48.0) pg·mL−1, respectively; P =.02] and RANKL [3.9 (3.8) vs 1.0 (0.4) pg·mL−1, respectively; P <.01] than girls. In girls, sclerostin significantly decreased 5-minute and 1-hour postexercise (χ2 = 12.7, P =.01), and RANKL significantly decreased 5-minute postexercise (χ2 = 19.1, P <.01) and continued to decrease up to 24-hour postexercise, with large effect sizes. In boys, DKK-1 significantly decreased 1-hour postexercise and remained lower than preexercise 24-hour postexercise (χ2 = 13.0, P =.01). OPG increased in both boys (χ2 = 13.7, P <.01) and girls (χ2 = 11.4, P =.01), with boys having significantly higher OPG at 5-minute and 1-hour postexercise, whereas in girls, this increase was only seen 24-hour postexercise. Conclusion: Plyometric exercise induces an overall anabolic osteokine response favoring osteoblastogenesis over osteoclastogenesis in both boys and girls although the timeline and mechanism(s) may be different. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is characterized by massive changes in neuronal excitation, from acute excitotoxicity to chronic hyper- or hypoexcitability. Nuclear calcium signaling pathways are involved in translating changes in synaptic inputs and neuronal activity into discrete transcriptional programs which not only affect neuronal survival and synaptic integrity, but also the crosstalk between neurons and glial cells. Here, we report the effects of blunting neuronal nuclear calcium signals in the context of TBI.Methods: We used AAV vectors to express the genetically encoded and nuclear-targeted calcium buffer parvalbumin (PV.NLS.mCherry) or the calcium/calmodulin buffer CaMBP4.mCherry in neurons only. Upon TBI, the extent of neuroinflammation, neuronal death and synaptic loss were assessed by immunohistochemistry and targeted transcriptome analysis. Modulation of the overall level of neuronal activity was achieved by PSAM/PSEM chemogenetics targeted to parvalbumin interneurons. The functional impact of neuronal nuclear calcium buffering in TBI was assessed by quantification of spontaneous whisking.Results: Buffering neuronal nuclear calcium unexpectedly resulted in a massive and long-lasting increase in the recruitment of reactive microglia to the injury site, which was characterized by a disease-associated and phagocytic phenotype. This effect was accompanied by a substantial surge in synaptic loss and significantly reduced whisking activity. Transcriptome analysis revealed a complex effect of TBI in the context of neuronal nuclear calcium buffering, with upregulation of complement factors, chemokines and interferon-response genes, as well as the downregulation of synaptic genes and epigenetic regulators compared to control conditions. Notably, nuclear calcium buffering led to a substantial loss in neuronal osteoprotegerin (OPG), whereas stimulation of neuronal firing induced OPG expression. Viral re-expression of OPG resulted in decreased microglial recruitment and synaptic loss. OPG upregulation was also observed in the CSF of human TBI patients, underscoring its translational value.Conclusion: Neuronal nuclear calcium signals regulate the degree of microglial recruitment and reactivity upon TBI via, among others, osteoprotegerin signals. Our findings support a model whereby neuronal activity altered after TBI exerts a powerful impact on the neuroinflammatory cascade, which in turn contributes to the overall loss of synapses and functional impairment. [ABSTRACT FROM AUTHOR]

Breast carcinomas are composed of cancer cells surrounded by various types of non-cancer cells such as fibroblasts. While active cancer-associated fibroblasts (CAFs) support tumor initiation and progression, quiescent breast stromal fibroblasts (BSFs) inhibit these effects through various cytokines such as osteoprotegerin (OPG). We showed here that OPG is upregulated in CAFs as compared to their adjacent normal tumor counterpart fibroblasts. Interestingly, breast cancer cells can upregulate OPG in BSFs in an IL-6-dependent manner through the IL-6/STAT3 pathway. When upregulated by ectopic expression, OPG activated BSFs through the NF-κB/STAT3/AUF1 signaling pathway and promoted their paracrine pro-carcinogenic effects in an IL-6-dependent manner. In addition, this increase in the OPG level enhanced the potential of BSFs to promote the growth of humanized orthotopic tumors in mice. However, specific OPG knock-down suppressed active CAFs and their paracrine pro-carcinogenic effects. Similar effects were observed when CAF cells were exposed to the pure recombinant OPG (rOPG) protein. Together, these findings show the importance of OPG in the activation of stromal fibroblasts and the possible use of rOPG or inhibitors of the endogenous protein to target CAFs as precision cancer therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: The lower jaw has a particular contribution to the human appearance, and so it is not uncommon for people to seek treatment in cases of its extreme growth. The orthodontist often selects to place intraoral devices in order to address the problem. This study used healthy young rats to guide their lower jaws backward. Measurements of biochemical molecules in blood that are related to bone metabolism did not reveal any statistically significant differences. However, noteworthy local microscopic alterations of the condyle were evidenced. They involved histological changes in bone structure and the thickness of cartilage. In conclusion, it seems that the procedure under study might not cause any severe organic disturbance in the lab animals under the conditions of the experiment. Only minor histological effects on condylar morphology were observed. The present study aimed to investigate any biochemical and histological changes of the rat condyle and mandible in animals that had sustained mandibular growth restriction. Seventy-two male Wistar rats were divided into two equal groups, experimental and control. Each group consisted of three equal subgroups. The animals were sacrificed 30, 60, and 90 days after the start of the experiment. Blood samples were collected from the eye, and the osteoprotegerin (OPG), Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL), and Macrophage Colony-Stimulating factor (MCSF)concentrations were measured by using enzyme-linked immunosorbent assay (ELISA) kits. A histological analysis was performed on the mandibular condyles. The blood serum values of OPG, RANKL, and MCSF did not exhibit any statistically significant difference between groups or subgroups. However, significant histological changes became evident after a histomorphometric condylar examination was performed. The Bone Surface/Total Surface ratio appeared reduced in the anterior and posterior regions of the condyle. In addition, the Posterior Condylar Cartilage Thickness was measured and determined to be significantly diminished. The present intervention that employed orthodontic/orthopedic devices did not prove to have any significant effect on the circulating proteins under study. Posterior displacement of the mandible may culminate only in local histological alterations in condylar cartilage thickness and its osseous microarchitecture. [ABSTRACT FROM AUTHOR]

BackgroundThe receptor activator of NF-κB ligand (RANKL), a member of the TNF ligand superfamily, is known to regulate bone metabolism. The expression of each component of the RANK/RANKL/osteoprotegerin (OPG) system in the intervertebral disc (IVD) has not been examined in detail. The purposes of this study were to examine the expression of the RANK/RANKL/OPG system and to evaluate the function of RANKL in the matrix metabolism of the rat IVD.MethodsSprague-Dawley, 12-week-old, male rats were used in this study. Anulus fibrosus (AF), nucleus pulposus (NP) and cartilaginous endplate (CEP) cells isolated from dissected thoracolumbar discs were monolayer-cultured. RANK/RANKL/OPG expression in rat IVDs was examined using real-time polymerase chain reaction (PCR) and immunohistochemical analysis (cultured cells and IVD tissues). To examine the effect of interleukin-1β (IL-1β) stimulation on the mRNA levels of RANK, RANKL and OPG, the cells were cultured with or without recombinant human IL-1β (rhIL-1β). To evaluate the effect of RANKL on the mRNA expression of catabolic factors (IL-1β, matrix metalloproteinase-3 (MMP-3) and MMP-13), the cells were cultured with RANKL in the presence or absence of rhIL-1β. The immunohistochemical expression of this system was also evaluated using human IVD tissues with different grades of degeneration.ResultsmRNA expression levels of RANK, RANKL, and OPG were clearly identified in AF, NP and CEP cells. Immunoreactivity to RANK, RANKL and OPG was distributed in the cell membranes and/or cytoplasm of the three types of cells. The mRNA level of RANKL was significantly upregulated by treatment with rhIL-1β of the three types of cells. Treatment with RANKL without rhIL-1β did not induce significant effects on the mRNA expression of catabolic factors by AF, NP and CEP cells. However, the expression was significantly upregulated by stimulation with RANKL in the presence of rhIL-1β. There was a general trend for more RANK/RANKL/OPG-positive cells in human IVD tissues in an advanced stage of degeneration compared to an early stage.ConclusionsOur study showed the possibility that the RANK/RANKL/OPG system may play a part in the process of intervertebral disc degeneration.

Introduction • Osteoporosis affects approximately 10% of the population worldwide. β-sitosterol (BSS), a major phytosterol in plants, has been claimed for centuries to have numerous medical benefits, including bone strengthening. This study aimed to find the benefit of BSS in treating osteoporosis according to traditional methods and to investigate the protective effect of BSS on glucocorticoid-induced osteoporosis in rats. Design • Wistar rats were randomly assigned to one of four groups: the control group, the dexamethasone (DEX) group and one of two BSS-treated osteoporosis groups (100 and 200 mg/kg). Blood samples and femur bones were collected for histopathology, immunohistochemistry, biochemical and mRNA expression analysis. Results • The results indicated that BSS (100 and 200 mg/kg) increased bone length, bone weight and bone mineral density (BMD) and suppressed DEX-induced reduction in body weight, dose-dependently. Mechanistically, BSS (100 and 200 mg/kg) treatment alleviated the increase of bone resorption markers and the decline of osteogenic markers, which might be partially mediated by regulation of nuclear factor kappa-β ligand/osteoprotegerin (RANKL/ OPG) and RunX2 pathways. The immunohistochemical inducible nitric oxide synthase (iNOS) results of the rats’ distal femur were negative in all groups. However, except in the DEX group, the endothelial nitric oxide synthase (eNOS) color reaction in osteoblasts was strongly positive in the other 3 groups. These results suggest that BSS showed promising effects in protection against glucocorticoid-induced osteoporosis by protecting osteoblasts and suppressing osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Background: External apical root resorption (EARR), an unwanted sequela of orthodontic treatment, is difficult to diagnose radiographically. Hence, the current scoping review was planned to generate critical evidence related to biomarkers in oral fluids, i.e. gingival crevicular fluid (GCF), saliva, and blood, of patients showing root resorption, compared to no-resorption or physiologic resorption. Methods: A literature search was conducted in major databases along with a manual search of relevant articles in the library, and further search from references of the related articles in March 2021. The initial search was subjected to strict inclusion and exclusion criteria according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Results: Following PRISMA guidelines, 20 studies were included in the final review. The studies included human clinical trials and cross-sectional and prospective studies with/without control groups with no date/language restriction. Various biomarkers identified in EARR included dentinal proteins, enzymes, cytokines, and salivary proteins. Severe resorption had higher dentin sialoprotein (DSP) and resorption protein concentrations as well as lower granulocyte-macrophage colony-stimulating factor (GM-CSF) as compared with mild resorption. Increased DSP and dentin phosphophoryn (DPP) expression was found in physiologic resorption. Compared to controls, resorbed teeth showed a higher receptor activator of nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG) ratio. In contrast, levels of anti-resorptive mediators (IL-1RA, IL-4) was significantly decreased. Differences in force levels (150 g and 100 g) showed no difference in resorption, but a significant rise in biomarkers (aspartate transaminase [AST] and alkaline phosphatase [ALP]) for 150 g force. Moderate to severe resorption in young patients showed a rise in specific salivary proteins, requiring further validation. Limitations of the studies were heterogeneity in study design, biomarker collection, sample selection, and confounding inflammatory conditions. Conclusions: Various biomarkers in biofluids indicate active resorption, while resorption severity was associated with DSP and GM-CSF in GCF, and a few salivary proteins. However, a robust study design in the future is mandated. [ABSTRACT FROM AUTHOR]

Objective: Osteoprotegerin is a glycoprotein that plays a major role in the regulation of bone turnover. The influence of parathyroid hormone, an important regulator of bone remodeling, on osteoprotegerin production is controversial. The purpose of the study was to assess the influence of parathyroid hormone on the circulating level of osteoprotegerin in patients with primary hyperparathyroidism by comparing it with healthy controls. Materials and Methods: Forty-four patients with biochemical verification of primary hyperparathyroidism scheduled for the surgical cure and 38 healthy subjects were included. Blood samples of the study group were taken before surgery. Levels of serum parathyroid hormone, osteoprotegerin, calcium, 25-hydroxyvitamin D [25(OH)D], and alkaline phosphatase were analyzed. Bone mineral density at the L1-L4 vertebrae and femoral neck was calculated by dual-energy X-ray absorptiometry. Results: Osteoprotegerin levels and bone mineral density values were significantly lower in patients than in the healthy subjects (P = .002 and P < .0001, respectively). There was no correlation between osteoprotegerin and parathyroid hormone in the groups. Osteoprotegerin was weakly correlated with bone mineral density in patients. No correlation was noted between osteoprotegerin and bone mineral density in the control group. Furthermore, osteoprotegerin levels were not correlated with calcium, 25(OH)D, and alkaline phosphatase levels in each group. Conclusion: The production of osteoprotegerin appears to be inhibited by parathyroid hormone in patients with primary hyperparathyroidism. A weak positive correlation found among osteoprotegerin and bone mineral density recommends that osteoprotegerin may be a molecule that impacts bone metabolism and finally bone mineral density. [ABSTRACT FROM AUTHOR]

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Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with an increased prevalence of subclinical atherosclerosis and cardiovascular risk. Angiopoietin‐2 (Ang‐2), asymmetric dimethylarginine (ADMA), and osteoprotegerin (OPG) are molecules related to endothelial dysfunction (ED) and atherosclerosis, but also to disease severity in patients with chronic inflammatory disorders. In this case–control study, we aimed to investigate serum Ang‐2, ADMA, and OPG levels in patients with HS, and to assess the potential relationship between these levels and disease severity. Seventy‐five patients with HS and 60 controls were assessed. Serum Ang‐2, ADMA, and OPG concentrations were determined in all participants. HS patients had significantly higher Ang‐2 and ADMA levels than controls after adjusting for confounders. Besides, Ang‐2 concentrations positively correlated with disease severity in the adjusted multivariable analysis. Nevertheless, serum OPG levels did not significantly differ between HS patients and controls. Our results indicate that serum Ang‐2 and ADMA levels are significantly increased in patients with HS. Furthermore, Ang‐2 might be a suitable marker of HS severity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Orthodontic treatment can change the levels of various cytokines in periodontal tissue, which promotes bone resorption on the tooth pressure side and bone formation on the tooth tension side. Changes in high glucose level and other inflammatory factor levels in diabetic patients induce an imbalance in bone metabolism where absorbed bone tissue is more than that formed. OBJECTIVE: To observe the effects of interleukin-10 and mechanical stimulation on the expressions of osteoprotegerin and receptor activator of nuclear factor kappa B ligand in human periodontal ligament cells under high glucose environment, and to explore the effect of interleukin-10 on bone remodeling of alveolar bone in diabetic patients under orthodontic force. METHODS: Human periodontal ligament cells were cultured by tissue explant method. According to the mechanical stimulation the cells received, the cells were divided into stress group (A, B, C, D subgroups) and tension group (E, F, G, H subgroups). Both stress and tension groups included four subgroups (lowglucose DMEM group, low-glucose DMEM group+interleukin-10 group, high-glucose DMEM group, high-glucose DMEM+interleukin-10 group). Cell supernatant was collected at 0, 12, 24, 48, and 72 hours after culture. The expressions of osteoprotegerin and receptor activator of nuclear factor kappa B ligand in the supernatant were detected by ELISA. RESULTS AND CONCLUSION: Pressure could decrease the expression of osteoprotegerin and increase the expression of receptor activator of nuclear factor kappa B ligand in human periodontal ligament cells, and decreased their ratio. High glucose could promote this process, while the effect of interleukin-10 was opposite to that of high glucose. Tension could increase the expression of osteoprotegerin, decrease the expression of receptor activator of nuclear factor kappa B ligand in human periodontal ligament cells, and increase their ratio. High glucose could inhibit this process, and interleukin-10 had an effect that was opposite to high glucose. To conclude, high glucose environment can reduce the expression of osteoprotegerin, increase the expression of receptor activator of nuclear factor kappa B ligand in human periodontal ligament cells, and decrease their ratio under mechanical stimulation. Whereas, interleukin-10 can antagonize the effect of high glucose. [ABSTRACT FROM AUTHOR]

Recently, a human mutation of OPG was identified to be associated with familial forms of osteoarthritis. This missense mutation (c.1205A = > T; p.Stop402Leu) occurs on the stop codon of OPG, which results in a 19-residue appendage to the C-terminus (OPG+19). The biochemical consequence of this unusual sequence alteration remains unknown. Here we expressed OPG+19 in 293 cells and the mutant OPG was purified to homogeneity by heparin affinity chromatography and size exclusion chromatography. We found that in sharp contrast to wildtype OPG, which mainly exists in dimeric form, OPG+19 had a strong tendency to form higher-order oligomers. To our surprise, the hyper-oligomerization of OPG+19 had no impact on how it binds cell surface heparan sulfate, how it inhibits RANKL-induced osteoclastogenesis and TRAIL-induced chondrocytes apoptosis. Our data suggest that in biological contexts where OPG is known to play a role, OPG+19 functions equivalently as wildtype OPG. The disease-causing mechanism of OPG+19 likely involves an unknown function of OPG in cartilage homeostasis and mineralization. By demonstrating the biochemical nature of this disease-causing OPG mutant, our study will likely help elucidating the biological roles of OPG in cartilage biology. [ABSTRACT FROM AUTHOR]

Purpose: Decreased baroreflex sensitivity (BRS) has been shown to be a marker of cardiovascular (CV) risk. In the present study, the difference in CV risk biomarkers in type 2 diabetes (T2D) patients receiving oral antidiabetic drugs (OAD) with and without hypertension has been assessed. Materials and methods: Ninety-two T2D patients on OAD without hypertension (control group) and eighty-eight diabetic patients with hypertension on OAD and antihypertensive drugs (test group) matched for age, gender, body mass index, serum glucose, glycated haemoglobin, and duration of the disease were recruited for the study. Their blood pressure (BP) variability including BRS, heart rate variability (HRV), insulin, lipid profile, osteoprotegerin (OPG), and tumor necrosis factor-α (TNF-α) were estimated. The association of various factors with BRS was assessed by Spearman correlation and multiple regression analysis. Results: BRS was decreased (13.90 ± 5.27 vs 6.76 ± 4.58), HRV sympathetic indices [LFnu, LF-HF ratio (1.30 ± 0.49 vs 1.93 ± 0.62)], HOMA-IR, atherogenic index of plasma (AIP), OPG (223.08 ± 103.86 vs 287.60 ± 121.36) and TNF-α were increased, and parasympathetic indices [TP (1012.90 ± 316.18 vs 625.88 ± 229.84), RMSSD, SDNN, NN50, pNN50] were decreased in the test group compared to control group. In control group, parasympathetic indices, AIP, OPG, and TNF-α had a significant correlation and OPG had an independent association (β − 0.344; p 0.004) with BRS. In test group, BP, LF-HF ratio, parasympathetic indices, AIP, OPG, and TNF-α had significant correlation, and TNF-α alone (β − 0.297; p 0.022) had an independent contribution to decreased BRS. Conclusion: Despite antidiabetic and antihypertensive treatments, T2D patients with hypertension had more cardiometabolic risks in comparison to normotensive T2D patients. Inflammation could be the inciting factor for rise in BP and decrease in BRS (CV risk) in hypertensive T2D patients. Hypertension in diabetes could attenuate the link of OPG to the reduction in BRS. Reduction in BRS could be a physiological marker of CV risk in T2D patients treated with OAD. [ABSTRACT FROM AUTHOR]