Osteoprotegerin Concentrations Research Articles

Osteoprotegerin and Inflammation in Incident Peritoneal Dialysis Patients.

Objectives: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family involved in processes in many inflammatory states. OPG concentration is enhanced in the majority of chronic kidney disease (CKD) patients and those undergoing renal replacement therapy. The aim of the study was to assess the relation of OPG and chronic inflammation in peritoneal dialysis (PD) patients and to evaluate whether OPG concentrations in plasma and dialysate were related to plasma and dialysate levels of proinflammatory mediators (interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), interleukin 33 (IL-33) and interleukin 1 receptor-like 1IL-1RL1 (IL-1RL1, sST2)). Methods: The study included 37 patients of the Peritoneal Dialysis Center, Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland, 4-6 weeks after the onset of peritoneal dialysis therapy. During a peritoneal equilibration test, plasma (at 2 h) and dialysate (at 4 h) OPG, IL-33, 1IL-1RL1 (sST2), IL-6 and hsCRP concentrations were determined. Results: Plasma concentration of OPG did not correlate with dialysate OPG level (Rs = 0.04, p = 0.8). There was a strong positive correlation between plasma OPG concentrations and plasma IL-1RL1 (sST2) (Rs = 0.41; p = 0.01), plasma IL-6 (Rs = 0.38; p = 0.01) and plasma hsCRP (Rs = 0.35; p = 0.02). Dialysate OPG concentrations were positively associated with dialysate IL-1RL1 (sST2) (Rs = 0.37; p = 0.02) and dialysate IL-6 levels (Rs = 0.44; p = 0.005). Multivariate analysis showed that higher IL-1RL1 (sST2) (ß = +0.38, p = 0.006), higher plasma hsCRP (ß = +0.32, p = 0.02) and older age (ß = +0.35, p = 0.01) were independent determinants of higher plasma OPG concentration and that higher concentrations of dialysate IL-6 (ß = +0.37, p = 0.02) were independent determinants of higher dialysate OPG concentration. Conclusions: Both plasma and dialysate OPG levels are associated with the severity of systemic and local inflammation illustrated by the plasma and dialysate concentrations of IL-1RL1 (sST2), hsCRP and IL-6, suggesting that OPG might have a pivotal role in explaining the milieu of systemic and intraperitoneal inflammation.

Osteoprotegerin and receptor activator of the nuclear factor kappa B ligand (RANKL) in healthy pubertal girls - relationships with physical growth and classical bone turnover markers.

Osteoprotegerin (OPG) is a trap receptor for the receptor activator of the nuclear factor kappa B ligand (RANKL). We aimed to determine the OPG and free soluble RANKL (sRANKL) concentrations in girls during puberty and their relationships with pubertal stage, growth rate and serum concentrations of estradiol, as well as classical bone formation (N-terminal propeptide of type I collagen (PINP), bone-specific alkaline phosphatase (BALP), osteocalcin (OC)) and bone resorption (C-terminal telopeptide of type I collagen (CTX)) markers. The semi-longitudinal study involved 88 healthy girls, aged 11.8-13.2 years. Their weight and height were measured twice at one-year intervals. Pubertal stages were assessed using the Tanner (T) scale. Blood samples were taken at the first examination. Serum concentrations of OPG, sRANKL, CTX and BALP were determined by enzyme-linked immunosorbent assay, estradiol and PINP by radioimmunoassay and osteocalcin by immunoradiometric assay. The one-year increase in height and weight of girls in the T2 and T3 pubertal stages was greater than that of girls in the T4 stage (p=0.000, p<0.03). OPG concentrations (T2: 4.04±0.62; T3: 4.31±0.79; T4: 4.46±0.84 pmol/L) sRANKL concentrations (T2: 0.22 (IQR 0.09-0.54); T3: 0.42 (IQR 0.22-0.79); T4: 0.35 (IQR 0.16-1.04) pmol/L) and sRANKL/OPG ratios (T2: 0.05 (IQR 0.03-0.13); T3: 0.11 (IQR 0.05-0.19); T4: 0.09 (IQR 0.05-0.19) did not differ significantly between pubertal stages. Concentrations of PINP, CTX, BALP and OC were higher in girls at T3 stage than at the T4 stage (p=0.000, p=0.001, p=0.046, p=0.038; respectively). Concentrations of sRANKL and OPG did not correlate with body weight, height, growth rate, or concentrations of estradiol, PINP, CTX, BALP and OC. There were correlations between the increase in height over one year and the concentrations of PINP (r=0.499, p=0.000), CTX (r=0.311, p=0.003) and BALP (r=0.224, p=0.036), as well as of estradiol (r=-0.473, p=0.000). Unlike PINP, OC, BALP, CTX or estradiol concentrations, sRANKL and OPG concentrations do not change in girls during puberty. Neither OPG nor sRANKL concentrations correlate with somatic characteristics and classical bone turnover markers concentrations.

Association of Serum Osteoprotegerin With Vascular Calcification, and Cardiovascular and Graft Outcomes in Kidney Transplant Patients: Results From the KNOW-KT.

Vascular calcification and stiffness contribute to increased cardiovascular morbidity in patients with chronic kidney disease. This study investigated associations between serum osteoprotegerin (OPG) levels and vascular calcification or stiffness to assess cardiovascular and graft outcomes in kidney transplant patients. The KoreaN cohort study for Outcome in patients With Kidney Transplantation was a prospective multicenter cohort study. Serum OPG levels were measured at baseline and 3 y after transplantation in 1018 patients. Patients were classified into high and low OPG groups according to median serum OPG levels. The median follow-up duration was 93.5 mo. The mean age was 45.8 ± 11.7 y and 62.9% were men. Patients with high OPG had significantly higher coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities than those with lower OPG; these parameters remained significant for 5 y after transplantation. The 3-y OPG levels were lower than baseline values ( P < 0.001) and were positively correlated ( r = 0.42, P < 0.001). Multivariate Cox regression analysis showed that high OPG levels were significantly associated with posttransplant cardiovascular events ( P = 0.008) and death-censored graft loss ( P = 0.004). Similar findings regarding posttransplant cardiovascular events ( P = 0.012) and death-censored graft loss ( P = 0.037) were noted in patients with high OPG at the 3-y follow-up. Mediation analyses revealed that coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities could act as mediators between serum OPG levels and posttransplant cardiovascular events. Serum OPG concentration is associated with vascular calcification and stiffness and could be a significant risk factor for cardiovascular outcomes and graft loss in patients undergoing kidney transplantation.

Soluble Receptor Activator of Nuclear Factor Ligand and Osteoprotegerin Levels in Gingival Crevicular Fluid among Cigarette Smokers and Non-smokers with and without Periodontitis.

This study aimed to measure and compare the levels of soluble receptor activator of nuclear factor ligand (RANKL) and osteoprotegerin (OPG) in the gingival crevicular fluid (GCF), as well as their ratio, in smokers and nonsmokers with periodontitis. Gingival crevicular fluid samples were collected using PerioPaper strips, from 150 individuals, who were categorized into three groups: current smokers with periodontitis stage III grades C and B (n = 50), nonsmokers with periodontitis stages I and II grade A (n = 50), and control healthy individuals (n = 50). The concentrations (pg/mL) of sRANKL and OPG in the GCF were measured by enzyme-linked immunesorbent assays (ELISA). The smokers' group exhibited the highest sRANKL (pg/mL) concentration as a subsequent lead to a higher sRANKL/OPG ratio. The healthy control group exhibited higher OPG and lower sRANKL concentration, subsequently, the sRANKL/OPG ratio was reduced compared with the other study groups. However, there was no statistical significance of sRANKL and its relative ratio between periodontitis stage III grades C and B, periodontitis stages I and II grade A, and healthy control individuals. There was a statistically significant positive moderate correlation between smoking duration (years) and the sRANKL (pg/mL) concentration and a statistically significant negative moderate correlation between OPG (pg/mL) concentration and cigarettes smoked per day. As a result, compared to the other research groups, smokers with periodontitis stage III grades C and B had greater GCF concentrations of sRANKL, lower OPG, and a higher sRANKL/OPG ratio. The difference in OPG (pg/mL) level was statistically significant. However, there was no statistically significant difference in sRANKL (pg/mL) or its relative ratio, sRANKL/OPG, across the groups. A characteristic that sets periodontitis apart is alveolar bone loss. Resorption is induced by RANKL and inhibited by OPG, resulting in a relative ratio. In light of this, the levels of RANKL and OPG may be helpful indicators for monitoring the activity of periodontal disease in both smokers and nonsmokers with and without periodontitis.

Inter-Donor Variability in Osteoclastogenesis and Responses to Osteoprotegerin (OPG), Von Willebrand Factor (vWF), and Factor VIII (FVIII)

Background: Patients with hemophilia A (HA) commonly exhibit reduced bone mineral density. We hypothesize that osteoclast differentiation may be influenced by the absence of factor VIII (FVIII), as well as other complement-associated proteins such as von Willebrand factor (vWF). Combinatory effects of vWF and recombinant FVIII (rFVIII) on osteoclast differentiation have been described previously, however the effects of rFVIII or vWF on osteoclast precursors across individual donors in the presence of osteoprotegerin (OPG), an important inhibitor of osteoclast differentiation, have not been systematically addressed. Aim: The main aim of this study is to investigate the effect of vWF, FVIII, or a combination of both factors, on osteoclastogenesis (induced by receptor activator of NF-κB ligand, RANKL) in differentiating osteoclasts from individual human donors, in the presence or absence of OPG. Methods: CD14+ monocytes (osteoclast progenitors) were isolated from male healthy donors and cultured for 11 days in medium with 10% fetal calf serum (FCS), according to established protocols. The response of these osteoclast precursors to RANKL and OPG was measured by culturing them under the following conditions: macrophage colony-stimulating factor (M-CSF) (25 ng/ml), M-CSF + RANKL (60 ng/ml) and M-CSF + RANKL + OPG (concentration range 30-60 ng/mL) with cells from each donor. Cells were stained for presence of tartrate-resistant acid phosphatase (TRAP), actin ring, and number of nuclei, and the osteoclast-occupied surface was measured using a semi-automated imaging and analysis protocol. Subsequently, cells were cultured either in 10% human serum (HS) or 10% FCS and exposed to vWF (5 or 10 IU/mL), rFVIII (10 IU/mL), or both vWF + rFVIII for 7, 11 or 14 days in the presence of M-CSF, RANKL and OPG. Morphology was assessed by the aforementioned stainings, TRAP enzymatic activity was determined in the cell culture supernatant, and cathepsin K (CATK) expression was measured using qPCR. The potential of vWF and/or rFVIII to decrease osteoclastogenesis in the presence of OPG was measured through osteoclast-occupied surfaces or osteoclast numbers, with or without TRAP enzymatic activity and/or CATK expression. Donors were categorized as OPG-responding or OPG-non-responding based on the relative reduction of osteoclast formation in the presence of OPG. Results: The initial response to RANKL and OPG was determined in 7 donors. Two OPG-non-responding (donors #1 and #2) and 5 OPG-responding donors (donors #3-7) were identified (Figure 1A). Most donors showed a reduced osteoclastogenesis in presence of OPG and vWF. In donor #2, in whom osteoclastogenesis in the presence of OPG was already low, a further reduction by vWF could not be achieved. Of note, a clear inhibition was observed in this donor without OPG (Figure 1B). The effects of rFVIII were more donor-dependent than those with vWF or vWF + rFVIII, with 4 of 7 donors showing reduced osteoclastogenesis. The results were influenced by the type of serum (HS or FCS) used. In all donors, and irrespective of the medium type, the combination of vWF + rFVIII reduced osteoclast formation, indicating a potentially beneficial effect of vWF + rFVIII compared with vWF or rFVIII alone (Figure 1B). Conclusion: Under inhibitory conditions (i.e. in the presence of OPG), rFVIII and vWF (alone or combined) decreased osteoclastogenesis in vitro. This may indicate that vWF and rFVIII, either alone or in combination, can influence the potency of OPG to inhibit osteoclastogenesis. However, this effect was not consistent in all donors. Currently, we are looking into the mechanisms that may explain the differential behavior of osteoclasts derived from OPG-responding and OPG-non-responding donors, as well as studying these effects in cells from patients with HA. We speculate that the absence of FVIII may lead to less efficient inhibition of OPG and increased osteoclastogenesis, which could explain lower bone mineral density observed in HA.

Peroxisome proliferator-activated receptor gamma and osteoprotegerin levels as an indicator and diagnostic predictor of endothelial dysfunction

Abstract Objectives Peroxisome proliferator-activated receptor gamma (PPAR-γ) modifies many cellular processes that contribute to atherosclerosis. The increased concentrations of osteoprotegerin (OPG) are related with coronary artery disease, calcification in vascular tissue, advanced atherosclerosis, and diabetic complications has been informed. The aim of our study was to define the relation among PPAR-γ Pro12Ala and, OPG and PPAR-γ in Peripheral Vascular Disease (PVD) and hypertension (HT). Also, it was aim to investigate the relationship between flow-mediated dilatation (FMD) in HT and ankle brachial index (ABI) in PVD in terms of endothelial dysfunction (ED). Methods Fifty-four patients with HT, 47 with PVD, and 52 healthy for the controls were included. Blood samples were used for analyzing PPAR-γ and OPG by Enzyme-Linked Immunosorbent Assay (ELISA), and biochemical assays. The PPAR-γ Pro12Ala was examined using TaqMan with PrimerProbMix. p value less than 0.05 was accepted as the limit of significance. Results The PPAR-γ was significantly decreased in both HT and PVD (p&lt;0.001). The serum concentrations of OPG were higher in HT (p&lt;0.001) and increased in diabetic ones (p&lt;0.05). CG genotype of PPAR-γ Pro12Ala was more frequent in HT patients (p&lt;0.001). In the HT patients, increased OPG and decreased PPAR-γ were found in CC (p&lt;0.001). In the PVD patients, PPAR-γ levels decreased in carrying with CC (p&lt;0.05). Conclusions It may be significant that increased OPG, as a marker of endothelial dysfunction, is found in HT. Moreover, decreased PPAR-γ in those who have to carry CC may be protective in both HT and PVD.

LMS-based continuous pediatric reference values for soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) in the HARP cohort

SummarySoluble RANKL (sRANKL) and osteoprotegerin (OPG) are regulators of osteoclast differentiation and activation, but adequate pediatric reference values are lacking. Here we provide LMS (Lambda-Mu-Sigma)-based continuous pediatric reference percentiles for sRANKL, OPG and sRANKL/OPG ratio that will allow calculation of standardized patient z-scores to assess bone modeling in children.PurposeSoluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) are regulators of osteoclast differentiation and activation and thus bone metabolic turnover in children. Adequate pediatric reference values for their serum/plasma concentrations are lacking. The development of Lambda-Mu-Sigma (LMS)-based continuous reference percentiles for laboratory parameters allow improved data interpretation in clinical practice.MethodsA total of 300 children aged 0.1–18 years (166 boys) were enrolled in the HAnnover Reference values for Pediatrics (HARP) study. sRANKL and OPG were assessed by ELISA. LMS-based continuous reference percentiles were generated using RefCurv software.ResultsLMS-based percentiles were established for sRANKL, OPG and sRANKL/OPG ratio, which were all found to be age-dependent. sRANKL and sRANKL/OPG associated with sex. In boys, sRANKL percentiles were highest during infancy, followed by a continuous decline until the age of 7 years and a second peak around age 12–13 years. In girls, a continuous, slow decline of sRANKL percentiles was noticed from infancy onwards until the age of 13 years, followed by a rapid decline until adulthood. OPG percentiles continuously declined from infancy to adulthood. The percentiles for sRANKL/OPG ratio paralleled those of sRANKL. Serum concentrations of sRANKL correlated with OPG and serum phosphate z-scores, while OPG concentrations inversely associated with standardized body weight, BMI, and urinary phosphate to creatinine ratio (each p < 0.05).ConclusionThis is the first report of LMS-based continuous pediatric reference percentiles for sRANKL, OPG and sRANKL/OPG ratio that allows calculation of standardized patient z-scores to assess bone metabolic turnover in children.

Changes of serum osteoprotegerin level in recurrent urolithiasis

Introduction. In our earlier research on the role of genetic factors in the development of recurrent urolithiasis, a significant relationship was found between the presence of single-nucleotide polymorphism rs3134057 in the osteoprotegerin (OPG) gene and the development of this disease. The above-mentioned single-nucleotide polymorphism is intronic, therefore, it is unable to involve the structure and functions of the OPG but to affect its expression. Thus, the study of serum OPG level may have diagnostic significance in recurrent urolithiasis.Objective. To study the relationship of serum OPG level with the presence of recurrent urolithiasis, as well as the effect of single nucleotide polymorphism rs3134057 on the OPG level.Materials &amp; methods. One hundred and fifteen volunteers were included in the study from January 2021 to January 2022. Of the 115 participants, 45 (main group #1) were diagnosed with recurrent urolithiasis and localisation of the main stone in one of the ureters, 28 participants (main group #2) had previously suffered a single episode of acute renal colic followed by surgical treatment or stone self-discharge and were stone-free at the time of the study. Forty-two control group respondents were free of urolithiasis, including family history of urolithiasis. The serum OPG levels was determined by enzyme immunoassay using the Human OPG ELISA kit ab100617 ("Abcam plc", Cambridge, UK) according to the manufacturer's advice.Results. The analysis revealed that the serum OPG levels were significantly higher in the main group #1 than in the control group (median: 9.02 vs. 3.635, p = 0.012). When analyzing the relationship between the concentration of OPG in serum and the AA + AG genotype versus GG according to rs3134057 of the OPG gene, no statistically significant difference was found (p &gt; 0.05). The same result was obtained when comparing groups with AA vs. AG vs. GG genotypes (p &gt; 0.05).Conclusion. The present study showed that an increased serum OPG level in patients with recurrent urolithiasis may indicate the presence of a relapse of the disease. Further study in large samples will finally confirm the significance of OPG as a marker of relapse, including in genetically determined forms.

Selected Parameters of Bone Turnover in Neuroendocrine Tumors-A Potential Clinical Use?

Currently, there are no effective markers to diagnose and monitor patients with neuroendocrine tumors (NETs). The aim of this study was to assess bone metabolism based on selected markers of bone turnover: OST, OPG, and IGFBP-3, in both the group of patients with NETs and the control group. Associations with selected sociodemographic, biochemical, and clinicopathological characteristics were examined. We also evaluated any potential associations between these markers and selected biochemical markers of NETs commonly used in clinical practice. The study group included 60 patients with GEP-NETs and BP-NETs, while the control group comprised 62 healthy individuals. The serum concentrations of OST, OPG and IGFBP-3 were assessed using ELISA. OST and OPG levels were significantly higher in the study group compared to the control group. In the study group, we observed a significant correlation between OPG and the clinical stage and chromogranin A. Additionally, an association was found between OPG and histological grade, Ki-67, and metastasis in GEP-NET cases. Markers of bone turnover cannot be used in the routine diagnostics of neuroendocrine tumors. Nonetheless, these markers may help evaluate the skeletal system in patients with NETs. Further research is needed to determine the utility of osteocalcin (OST) and osteoprotegerin (OPG) as potential biomarkers for neuroendocrine tumors.

Clinical significance of Osteoprotegerin, Vitamin D, Obestatin and some biochemical variables in Kidney failure Patients

Chronic kidney disease (CKD) is described as an abnormalities of renal function, existing for a long period of time. By reason of the early grades of Chronic kidney disease can be experiences no symptoms, its premature identification is strenuous. initial stage CRD can cause various complications, such as anemia, matabolyic disorders of bone mineral. The study was done to assess the effect the chronic renal disease stage on the Osteoprotegerin, 1,25 dihydroxyvitamin D, Obestatin levels and some biochemical parameters in patients not undertaken dialysis therapy. In this case-control study fifty-five patients with Kidney failure and fourty healthy people were examined. Circulating concentrations of Osteoprotegerin, 1,25 dihydroxyvitamin D and Obestatin were estimated by ELIZA technique, serum urea, uric acid, total protein and total calciumu were estimated enzymatically using spectrophotometer.&#x0D; Serum concentration of Osteoprotegerin, Obestatin, renal function markers in patients group were higher (328.3±41.68 pg/mL; 15.52±4.28pg/mL; 183.2±10.35 mg/dL; 8.88±0.54 mg/dL; 6.57±0.22 mg/dL) respectively in comparison to the control group (172.6±55.48 pg/mL; 11.64±3.26 pg/mL; 33.45±1.08 mg/dL; 0.95±0.03 mg/dL; 4.35±0.22 mg/dL) respectively. Vitamin D, Total Calcium and Total Proteins level in patients group were lower(24.49±2.53 ng/mL; 8.06±0.18 mg/dL; 6.49±0.12 g/dL) respectively as compared to controls (57.11±12.39 ng/mL; 10.15±0.23 mg/dL; 6.82±0.10 g/dL) respectively. The current study reveals that circulating levels of Osteoprotegerin Obestatin are remarkably linked with the existence of renal failure, the current data identify a high prevalence deficiency and insufficiency of 1,25 dihydroxyvitamin D in patients with moderate and severe Chronic nephropathy.

#3388 ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY, PHYSICAL FUNCTION AND BONE METABOLISM MARKERS IN HAEMODIALYSIS PATIENTS: A PRELIMINARY CROSS-SECTIONAL STUDY

Abstract Background and Aims Chronic kidney disease (CKD) patients suffering from end-stage renal disease often undergo dialysis treatment. Haemodialysis (HD) patients spend most of their time in sedentary behaviour, having therefore poor physical function, as well as frequently develop mineral and bone disorders due to disease-induced systemic alterations such as abnormally high bone resorption rates exceeding bone formation. In healthy individuals, there is considerable evidence highlighting the associations between physical activity (PA), physical function (PF), and bone health. In HD patients, however, evidence on the association between these variables is still scarce. Therefore, the present preliminary study seeks to characterise HD patients in terms of their PA and PF, and to identify any associations between these and markers of bone metabolism. Method A cross-sectional design study recruited 88 adult HD patients (males: 68%, age: 66±14 years, dialysis vintage: 42±52 months) from three clinics in Portugal. Resting blood samples were collected from the patients’ fistula at the start of the second dialysis session of the week. Plasma levels of the bone markers tartrate-resistant acid phosphatase 5b (TRAP-5b) (IDS, Tyne and Wear, UK), and sclerostin (SOST) and receptor activator of nuclear factor kappa-Β ligand (RANKL) (Biomedica Immunoassays, Vienna, Austria) were measured by commercially-available enzyme-linked immunosorbent assays (ELISA), and osteocalcin (OCN) (Biogen, Madrid, Spain) and osteoprotegerin (OPG) (R&amp;D Systems, Abingdon, UK) via DuoSet ELISA kits. PF was assessed by completing the Sit to Stand 60 (STS60), the STS5, the Incremental Shuttle Walk Test (ISWT), the Timed Up and Go (TUG), and handgrip strength (HGS). All participants worn tri-axial accelerometers continuously for a week to estimate PA levels. Results Accelerometers were worn for an average 13±2h/day and data showed that 81±11% of the time was spent in sedentary behaviour, and 18±10% in light PA. Associations between PA, PF and markers of bone metabolism are described in Table 1. Weekly sedentary time was associated with reduced agility (TUG), muscle endurance (STS60, ISWT), and muscle power and strength (STS5), whereas light PA levels were associated with an increment in overall PF. Also, light PA levels were associated with decreased TRAP-5b and OPG, but elevated circulating OCN, supporting a potential modulatory effect of PA on bone turnover. Decreased overall PF were associated with increased concentrations of OPG, with muscle endurance and strength associated with increased circulating TRAP-5b. Conclusion Our data suggests that sedentarism may be responsible for a reduced PF, which in turn was associated with increased inhibition of osteoclastogenesis via OPG activity. Yet, a rather small increase in PA levels may lead to PF gains and could be a trigger for OCN activity and TRAP-5b inhibition. Therefore, increasing PA levels may modulate bone metabolism through mechanisms that favor bone formation.

Plasma osteoprotegerin predicts adverse cardiovascular events in stable coronary artery disease: the PEACE trial.

Osteoprotegerin (OPG) is a secretory glycoprotein and participates in the progression of atherosclerotic lesions. We aim to explore the relationship between OPG and the prognosis of coronary artery disease (CAD). Plasma OPG concentrations were measured in 3,766 patients with stable CAD enrolled in the PEACE trial. The PEACE trial (NCT00000558) group followed up the patients and examined their future clinical outcomes. In summary, 208 (5.5%) primary outcomes occurred, 295 patients (7.8%) died from all-cause death, 128 (3.4%) died from cardiovascular causes, and 94 (2.5%) experienced heart failure during a median follow-up of 1,892 days. In addition, we found that higher plasma levels of OPG were associated with a higher incidence of all-cause death, cardiovascular death, and heart failure, even after adjusting clinical cofounders. It was demonstrated that elevated plasma OPG levels were associated with an increased incidence of all-cause death, cardiovascular death, and heart failure in patients with stable CAD. https://clinicaltrials.gov/ct2/show/NCT00000558?term=NCT00000558&draw=2&rank=1, identifier: NCT00000558.

Promotion of longitudinal bone growth by the intake of oat and green onion root water extracts in weaning rats through stimulating growth hormone secretion and elevating gut microbiota related to nervous system-related pathway

We determined whether oral oat and green onion water extracts (GOO) supplementation could stimulate longitudinal bone growth in weaning rats. Fistuloside A, B, and C in the green onions and 26-desglucoavenacoside A and B and avenacoside A in the oats lowered the binding energy of growth differentiation factor-5 (GDF5) and insulin-like growth factor-1 receptor (IGF1R). After a 4-week treatment, serum growth hormone (GH) and osteoprotegerin concentrations in the High-GOO group (500 mg/kg body weight) were similar to those of the Positive-control. The femur and tibia lengths promoting the proliferative and hypertrophic zones of the growth plate in the High-GOO were also similar to Positive-control. Along with increasing serum propionate and butyrate concentrations, cecal bacteria in the High-GOO were higher in virus infection, steroid and sesquiterpenoid biosynthesis, and nervous system-related pathways than the Control in the metagenome function. It suggested that gut bacteria potentially enhanced bone growth by improving immunity and neurological activity. In conclusion, GOO increased leg length by enhancing the proliferation of the growth plate as much as GH treatment by preventing gut dysbiosis.

Effect of leukocyte-platelet-rich fibrin (L-PRF) on the rate of orthodontic tooth movement and expression of various biomarkers in gingival crevicular fluid.

To assess the outcome of leukocyte-platelet-rich fibrin (L-PRF) on the rate of maxillary canine retraction and its correlation with the levels of Receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), and RANKL:OPG in the gingival crevicular fluid (GCF) during comprehensive orthodontic treatment. Eighteen females who required all 1st premolars extraction for the correction of their class I bimaxillary protrusion malocclusions were included. The L-PRF plugs were placed in the experimental side 1st premolar extraction sockets. Canine retraction was performed by sliding mechanics. Canine retraction was assessed from the maxillary study models prepared just before the extraction (T0) and then at 1week (T1), 2weeks (T2), 4weeks (T3), and 8weeks (T4) after the 1st premolar extraction and placement of L-PRF plugs. The concentrations of RANKL and OPG in the GCF were evaluated at T0, T1, T2, T3, and T4. In experimental sides, the amount of canine retraction was statistically more during the T0-T1, T1-T2, and T2-T3 periods. The mean concentration of RANKL at T1, T2, and T3 was significantly more in the experimental sides. The mean concentration of OPG was significantly less in the experimental sides at T2, T3, and T4. The RANKL:OPG was significantly more in the experimental sides at T1, T2, T3, and T4. No significant correlation was found between amount of canine retraction and concentration of RANKL and OPG and RANKL to OPG ratio in GCF. The L-PRF accelerated the rate of maxillary canine retraction by 0.28mm over an 8-week period. The L-PRF favored the local osteoclastogenesis by enhancing the RANKL and suppressing the OPG concentrations. There was no significant correlation between the rate of maxillary canine retraction and expression of RANKL, OPG, and RANKL:OPG in GCF. The Clinical Trials Registry of India (Reg. No. CTRI/2020/10/028390, Date-13.10.2020).

Postdiagnosis circulating osteoprotegerin and TRAIL concentrations and survival and recurrence after a breast cancer diagnosis: results from the MARIE patient cohort

BackgroundExperimental studies suggest a role for osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in mammary tumor development and progression. These biomarkers have been minimally investigated with respect to outcomes in breast cancer patients.MethodsOPG and TRAIL were evaluated in blood samples collected from 2459 breast cancer patients enrolled in the MARIE study, a prospective population-based patient cohort, at median of 129 days after diagnosis. Participants were between ages 50 and 74 at diagnosis and recruited from 2002 to 2005 in two regions of Germany. Follow-up for recurrence and mortality was conducted through June 2015. Delayed-entry Cox proportional hazards regression was used to assess associations between OPG and TRAIL with all-cause and breast cancer-specific mortality, and recurrence, both overall and by tumor hormone receptor status.ResultsMedian follow-up time was 11.7 years, with 485 deaths reported (277 breast cancer-specific). Higher OPG concentrations were associated with a higher risk of all-cause mortality (hazard ratio for 1-unit log2-transformed concentration (HRlog2) = 1.24 (95% confidence interval 1.03–1.49). Associations were observed in women diagnosed with ER-PR- tumors or discordant hormone receptor status (ER-PR-, HRlog2 = 1.93 (1.20–3.10); discordant ERPR, 1.70 (1.03–2.81)), but not for women with ER + PR + tumors (HRlog2 = 1.06 (0.83–1.35)). OPG was associated with a higher risk of recurrence among women with ER-PR- disease (HRlog2 = 2.18 (1.39–3.40)). We observed no associations between OPG and breast cancer-specific survival, or for TRAIL and any outcome.ConclusionsHigher circulating OPG may be a biomarker of a higher risk of poor outcome among women diagnosed with ER- breast cancer. Further mechanistic studies are warranted.

Role of osteoprotegerin rs3102735 gene polymorphism in acute ischemic stroke patients

BackgroundIschemic stroke ranks third among leading causes of death and disability. Both endothelial and vascular smooth muscle cells generate osteoprotegerin (OPG). Ischemic stroke and its severity may be enhanced by the OPG rs3102735 gene polymorphism. Our research aims to investigate OPG rs3102735 gene polymorphism role in ischemic stroke risk and to assess its association with stroke severity at presentation and degree of vascular stenosis and evaluate its potential as a predictor of stroke severity. Fifty people with acute ischemic stroke as well as fifty controls were studied. The NIHSS and ASPECTS were utilized to evaluate stroke severity and the infarction size, respectively. All subjects underwent extracranial carotid duplex study and molecular assessment for genotyping of OPG rs3102735) gene polymorphism.ResultsStroke patients had markedly higher concentrations of OPG in the plasma than controls (311.60 ± 109.48 versus 240.20 ± 75.96 mmol/ml, p = 0.001). The optimal plasma OPG cutoff value for the predicting the occurrence of stroke was determined to be > 250 mmol/ml, the 95% confidence interval (CI) was (0.625–0.843), sensitivity was 68% and specificity was 72%. Ischemic stroke had a significantly different genotype distribution for the OPG rs3102735 gene polymorphism than did controls (36 CC, 13 CT, and 1 TT) versus (28 CC, 15 CT, and 7 TT) respectively. Stroke patients had a significantly greater CC + CT genotype than controls did (P = 0.041), also they had a higher propensity for carrying the C allele than the T allele (P = 0.017). Carotid intima medium thickness and the NIHSS both had positive correlations with OPG serum level (r = 0.39, p = 0.02 and r = 0.4, p = 0.02, respectively), whereas ASPECTS had an inversed correlation (r = − 0.65, p = 0.001).ConclusionsThe current study shows that as an independent risk factor, increased plasma OPG level, may participate in the atherothrombotic ischemic stroke pathophysiology, in addition, genetic variants in the OPG gene (rs3102735) are a separate risk factor for large artery atherosclerosis and plasma OPG level can serve as a biomarker to determine the severity of a stroke.

Randomized clinical trial on the effect of intermittent vibrational force application during orthodontic treatment with aligners on RANKL and OPG concentrations in crevicular fluid.

Application of intermittent forces by vibration is proposed as an easy-to-use accelerator of dental movement. The purpose of this study was to determine the effect of intermittent vibrational force application during orthodontic aligner treatment on receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG) concentrations in crevicular fluid as markers of bone remodeling. This three-arm parallel randomized clinical trial included 45 candidates for malocclusion treatment with aligners, randomly assigned to: Group A (vibrational forces from onset of treatment); Group B (vibrational forces at 6 weeks after treatment onset); or Group C (no vibration). The frequency of aligner adjustment also differed among groups. At different time points, a paper tip was used to draw crevicular fluid samples from a moving lower incisor for RANKL and OPG analysis using ELISA kits. Mixed-model ANOVA found no significant differences in RANKL (A: p=0.31, B: p=0.8, C: p=0.49) or OPG (A: p=0.24, B: p=0.58, C: p=0.59) over time in any group or as a function of the application/non-application of vibration or the frequency of aligner adjustments. Application of this accelerator device did not significantly affect bone remodeling in patients undergoing orthodontic treatment with aligners. However, a nonsignificant improvement in biomarker concentrations was observed when aligners were changed every 7 days and vibration was also applied. Further research is warranted to establish protocols for the application of vibration and the timing of aligner adjustments.

Association of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease and retinopathy in type 2 diabetes.

Novel biomarkers of vascular disease in diabetes could help identify new mechanistic pathways. Osteocalcin, osteoprotegerin, and osteopontin are key molecules involved in bone and vascular calcification processes, both of which are compromised in diabetes. We aimed to evaluate possible associations of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease (CVD) and diabetic retinopathy (DR) among people with type 2 diabetes (T2D). Osteocalcin, osteoprotegerin, and osteopontin concentrations were measured at enrolment in 848 participants with T2D from the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study (ClinicalTrials.gov: NCT02311244). Logistic regression models and propensity score matching were used to assess possible associations of osteocalcin, osteoprotegerin, and osteopontin with a history of CVD and with evidence of any grade of DR adjusting for confounders. Previous CVD was reported in 139 (16.4%) participants, while 144 (17.0%) had DR. After adjusting for possible confounders, osteocalcin but not osteoprotegerin or osteopontin concentrations were associated with a history of CVD (Odds Ratio [OR] and 95% CI for one standard deviation (SD) increase in osteocalcin concentrations (natural log): 1.35 (1.06-1.72), p=0.014). Associations with prevalent DR were seen for osteoprotegerin (OR for one SD increase in osteoprotegerin concentrations (natural log): 1.25 (1.01-1.55), p=0.047) and osteopontin (OR for one SD increase in osteopontin concentrations (natural log): 1.25 (1.02-1.53), p=0.022), but not osteocalcin. In T2D, higher serum osteocalcin concentrations are associated with macrovascular complications and higher osteoprotegerin and osteopontin concentrations with microvascular complications, suggesting that these osteokines might be involved in pathways directly related to vascular disease.

Comparative study of the synovial levels of RANKL and OPG in rheumatoid arthritis, spondyloarthritis and osteoarthritis

IntroductionIn chronic arthropathies, there are several mechanisms of joint destruction. In recent years, studies have reported the implication of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in the process of activation and differentiation of osteoclasts, a key cell in the development of bone erosion. The RANKL/OPG ratio is increased in the serum of patients with malignant diseases and lytic bone disease, as well as rheumatoid arthritis (RA). The objective of this study was to measure and compare the concentrations of OPG and RANKL in the synovial fluid (SF) of patients with rheumatoid arthritis, spondyloarthritis (SpA) and osteoarthritis (OA).MethodsThis was an observational and cross-sectional study with 83 patients, 33 with RA, 32 with SpA and 18 with OA, followed up regularly in the outpatient clinics of the Rheumatology Department of the Clinics Hospital of the Ribeirão Preto Medical School-USP. All patients were assessed for indications for arthrocentesis by the attending physicians at the time of SF collection and were evaluated for demographic variables and medication use. Disease activity was assessed in individuals with RA and SpA. The quantification of SF OPG and RANKL levels was performed by ELISA, and the correlations of the results with clinical, laboratory and radiological parameters were assessed.ResultsWe found no statistically significant difference in the RANKL and OPG levels among the groups. Patients with RA showed a positive correlation between the SF cell count and RANKL level (r = 0.59; p < 0.05) and the RANKL/OPG ratio (r = 0.55; p < 0.05). Patients with OA showed a strong correlation between C-reactive protein (CRP) and the RANKL/OPG ratio (r = 0.82; p < 0.05). There was no correlation between the OPG and RANKL levels and markers of inflammatory activity or the disease activity index in patients with RA or SpA.ConclusionWithin this patient cohort, the RANKL/OPG ratio was correlated with the SF cell count in patients with RA and with serum CRP in patients with OA, which may suggest a relationship with active inflammation and more destructive joint disease.

Influence of Different Orthodontic Brackets on Cytokine and Cortisol Profile

Background and Objectives: Orthodontic tooth movement (OTM) requires bone remodeling resulting from complex processes of aseptic inflammation. Recent studies have confirmed close interaction between the immune and skeletal systems. In addition, various orthodontic appliances including fixed systems affect the sublingual microbial composition, and the likelihood of developing inflammatory reactions of the gums is high, especially early in the treatment period. It is known that these systems have both positive and negative effects on the humoral and cellular immune responses. The main aim of the study was to evaluate the influence of self-ligating and conventional brackets on the salivary concentrations of cytokines (IL-6, osteoprotegerin (OPG), TNF-alpha, and IFN-gamma) and cortisol as a marker of stress. Materials and Methods: Forty patients were analyzed at baseline (T0) and 2 months (T2) after fixing self-ligating (Ormco Damond Q) and conventional brackets (Ormco Mini Diamond). Salivary cytokine and cortisol concentrations were evaluated by commercial ELISA kits. Results: Outcomes of our study showed that after two months of treatment with either of these brackets, IFN-gamma and IL-6 levels did not change. However, TNF-alpha decreased with self-ligating brackets (13.36 to 8.32, p = 0.002). The self-ligating bracket system also affects OPG concentration and cortisol levels 2 months after orthodontic activation. The level of OPG in the group of self-ligating brackets decreased significantly (8.55 to 2.72, p = 0.003). Cortisol concentration was significantly higher in the self-ligation group (25.72 to 48.45, p = 0.001) due to the effect of sustained strength movements. Conclusions: Thus, the use of self-ligating and conventional brackets has a different effect on the concentration of cortisol and cytokines (OPG and TNF-alpha) in saliva 2 months after their fixation. Further longitudinal studies are necessary to explore why OPG levels are decreased in case of self-ligating cases and how OPG levels are related to clinical improvement.