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High risk of cardiovascular events is among leading problems in chronic kidney disease (CKD). Serum Klotho is supposed to be cardio- and nephroprotective; modification of its levels may be important in CKD.To evaluate the impact of vitamin D receptor activators (VDRA) on Klotho serum levels in CKD 3b4 stages patients.Study included 90 CKD 3b4 stages patients who had elevated serum levels of parathyroid hormone (PTH). From them, 47 patients (group 1) started to treat with the selective VDRA (zemplar 1 mcg/day), and 43 patients (group 2) started to treat with non-selective VDRA (alfacalcidol 0.25 mcg/day). At baseline and after 12 months we conducted routine examination, serum Klotho measurement, and broad cardiovascular examination.The patients who managed to maintain a target serum PTH level, had higher Klotho serum level (p=0.037) at the end of the study. Patients who used selective VDRA significantly more often reached the target PTH level (p=0.032), had higher serum Klotho levels (p=0.037), and glomerular filtration rate (eGFR) level (p=0.048) than patients who used non-selective VDRA. In addition, patients treated with alfacalcidol more than 6 months, more often had hypercalcemia (p=0.047) and hyperphosphatemia (p=0.035). Group 2 showed higher: pulse wave velocity (p=0.051), left ventricular myocardial mass index (p=0.033), and more advanced heart valve calcification (p=0.038).Successful parathyroid hormone level control with vitamin D receptor activators was associated with higher serum Klotho, selective agents having shown greater effect. Long-term treatment with selective vitamin D receptor activators may contribute to cardiovascular calcification prevention by modifying Klotho levels.Обоснование. Высокий риск сердечно-сосудистых событий остается одной из ведущих причин смертности у пациентов с хронической болезнью почек (ХБП). В то же время установлено, что циркулирующая форма белка Клото обладает выраженными кардио- и нефропротективными свойствами. Цель. Оценить влияние активаторов рецепторов витамина D (АРВД) на сывороточный уровень Клото у пациентов с ХБП стадии 3b4. Материалы и методы. В исследование включены 90 пациентов с ХБП стадии 3b4, имеющих на момент скрининга повышенный уровень паратиреоидного гормона (ПТГ). Из них 47 пациентов (1-я группа) начали лечение селективным АРВД (Земплар 1 мкг/сут), а 43 пациента (2-я группа) неселективным АРВД (альфакальцидол 0,25 мкг/сут). Исходно и через 12 мес, в дополнение к обычному обследованию при ХБП, изучали уровни Клото в сыворотке крови и провели расширенное сердечно-сосудистое обследование. Результаты. Пациенты, которым удалось достичь и поддерживать целевой уровень ПТГ, имели более высокие уровни Клото в сыворотке крови (p=0,037). Пациенты группы 1 значительно чаще достигали целевого уровня ПТГ (p=0,032), имели более высокие уровни Клото (p=0,037) и расчетной скорости клубочковой фильтрации (p=0,048), чем пациенты группы 2. Кроме того, у пациентов, получавших альфакальцидол более 6 мес, чаще наблюдались гиперкальциемия (p=0,047) и гиперфосфатемия (p=0,035), а также кальцификация клапанов сердца (p=0,048), увеличение скорости пульсовой волны (p=0,024), индекса массы миокарда левого желудочка (p=0,033) и частоты развития гипертрофии левого желудочка (p=0,048). Заключение. У пациентов с ХБП, которым удалось достичь и поддерживать целевой уровень ПТГ в крови, наблюдались более высокие уровни Клото. Использование селективных АРВД связано как с более высокой частотой достижения целевых уровней ПТГ в сыворотке, так и с более высокими уровнями Клото, чем использование неселективных АРВД.

ObjectiveTo evaluate changes in bone turnover and bone mineral density (BMD) in patients with rheumatoid arthritis (RA) receiving glucocorticoids, after discontinuation of denosumab for 12 months.MethodsWe conducted a randomized, double-blind, placebo-controlled, phase II study of RA patients. Patients received placebo, denosumab 60 mg, or denosumab 180 mg every 6 months for 12 months and were followed up for an additional 12 months after discontinuation, during which no bone loss prevention therapy was instituted. Changes from baseline in serum C-terminal telopeptide of type I collagen (CTX), serum procollagen type I N-terminal propeptide (PINP), and lumbar spine and total hip BMD were evaluated.ResultsIn this post hoc analysis of patients treated with glucocorticoids at study baseline (n=82), levels of CTX and PINP decreased significantly from baseline in both denosumab groups. Following denosumab discontinuation, CTX returned to baseline and was not significantly different from the placebo group 6 and 12 months after discontinuation. Median percentage changes from baseline PINP in those treated with denosumab 60 mg were -0.16% and 15.3% at 6 and 12 months, respectively, after discontinuation (P=0.062 and P=0.017, versus placebo); corresponding changes with denosumab 180 mg were 9.0% and 75.8%, respectively (P=0.018 and P=0.002 versus placebo). Compared to placebo, lumbar spine and total hip BMD increased in patients receiving denosumab and returned to baseline 12 months after discontinuation. No osteoporotic fractures were reported during treatment or in the off-treatment period.ConclusionIn this analysis of short-term denosumab use in RA patients receiving glucocorticoids, denosumab discontinuation resulted in a gradual increase in bone turnover, which was associated with a return to baseline lumbar spine and total hip BMD.

Biomarkers represent promising aids in periodontitis, host-mediate diseases of the tooth-supporting tissues. We assessed the diagnostic potential of matrix metalloproteinase-8 (MMP-8), tartrate-resistant acid phosphatase-5 (TRAP-5), and osteoprotegerin (OPG) to discriminate between healthy patients&rsquo, mild and severe periodontitis sites. Thirty-one otherwise healthy volunteers with and without periodontal disease were enrolled at the Faculty of Dentistry, University of Chile. Periodontal parameters were examined and gingival crevicular fluid was sampled from mild periodontitis sites (M, n = 42), severe periodontitis sites (S, n = 59), and healthy volunteer sites (H, n = 30). TRAP-5 and OPG were determined by commercial multiplex assay and MMP-8 by the immunofluorometric (IFMA) method. STATA software was used. All biomarkers showed a good discrimination performance. MMP-8 had the overall best performance in regression models and Receiver Operating Characteristic (ROC) curves, with high discrimination of healthy from periodontitis sites (area under the curve (AUC) = 0.901). OPG showed a very high diagnostic precision (AUC &ge, 0.95) to identify severe periodontitis sites (S versus H + M), while TRAP-5 identified both healthy and severe sites. As conclusions, MMP-8, TRAP-5, and OPG present a high precision potential in the identification of periodontal disease destruction, with MMP-8 as the most accurate diagnostic biomarker.

Periodontal diseases are chronic, infectious, inflammatory diseases that have a multifactorial character in terms of aetiology and pathogenesis. Periodontal diseases are divided into two major categories as gingivitis and periodontitis both of which are chronic infectious and inflammatory diseases. Microorganisms and/or their virulence factors trigger the host response and the activated immune cells cause periodontal tissue destruction. There are periods of active periodontal tissue destruction and quiescent periods in between them. This chapter provides an outline of the nature of periodontal diseases. Understanding the nature of periodontal diseases is mandatory in order to develop more precise diagnostic and also therapeutic methods.

Due to their potent immunomodulatory anti-inflammatory properties, synthetic glucocorticoids (GCs) are widely utilized in the treatment of chronic inflammatory disease. In this review, we examine our current understanding of how chronic inflammation and commonly used therapeutic GCs interact to regulate bone and muscle metabolism. Whilst both inflammation and therapeutic GCs directly promote systemic osteoporosis and muscle wasting, the mechanisms whereby they achieve this are distinct. Importantly, their interactions in vivo are greatly complicated secondary to the directly opposing actions of GCs on a wide array of pro-inflammatory signalling pathways that underpin catabolic and anti-anabolic metabolism. Several clinical studies have attempted to address the net effects of therapeutic glucocorticoids on inflammatory bone loss and muscle wasting using a range of approaches. These have yielded a wide array of results further complicated by the nature of inflammatory disease, underlying the disease management and regimen of GC therapy. Here, we report the latest findings related to these pathway interactions and explore the latest insights from murine models of disease aimed at modelling these processes and delineating the contribution of pre-receptor steroid metabolism. Understanding these processes remains paramount in the effective management of patients with chronic inflammatory disease.

Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we aimed to elucidate the fibrotic regulation of OPG production and its possible function in human and mouse livers. OPG levels were significantly higher in lysates of human and mouse fibrotic livers compared to healthy livers. Hepatic OPG expression localized in cirrhotic collagenous bands in and around myofibroblasts. Single cell sequencing of murine liver cells showed hepatic stellate cells (HSC) to be the main producers of OPG in healthy livers. Using mouse precision-cut liver slices, we found OPG production induced by transforming growth factor β1 (TGFβ1) stimulation. Moreover, OPG itself stimulated expression of genes associated with fibrogenesis in liver slices through TGFβ1, suggesting profibrotic activity of OPG. Resolution of fibrosis in mice was associated with decreased production of OPG compared to ongoing fibrosis. OPG may stimulate fibrogenesis through TGFβ1 and is associated with the degree of fibrogenesis. It should therefore be investigated further as a possible drug target for liver fibrosis or biomarker for treatment success of novel antifibrotics.

Objective: Besides its hematopoietic function, erythropoietin (EPO) may protect tissues from degenerative disorders. As such, EPO and its receptors were revealed in nonhematopoietic cells, including stromal and endometrial epithelial cells. However, the role of EPO in endometrial disorders is still unknown. Here, we aimed to examine the role of EPO and its receptor activation in the development of endometriosis in rats. Material and Methods: Animals were treated with EPO, darbepoietin (the synthetic form of EPO) or EPO’s receptor activator, methoxy polyethylene glycol-epoetin beta (MIRCERA), after development of endometriosis. Endometriosis was induced by estrogen-administration following surgical attachment of endometrial surface on the inner abdominal wall. Treatments were started 3 weeks after induction of endometriosis and continued for the following 3 weeks. For the analysis of recurrence of endometriosis, additional analyses were conducted 3 weeks after cessation of treatments. Results: As compared with vehicle-treated animals, lesion size was reduced significantly and recurrence of endometriosis was not observed in all treatment groups. Histopathologic examination revealed that EPO and darbepoietin were more effective than MIRCERA- and vehicle-treated animals. Conclusion: Here we provide evidence that EPO is a promising candidate for the treatment of endometriosis. Our histopathologic results in particular indicate that EPO is more effective than its receptor activator MIRCERA in the development endometriosis. © 2019 by the Turkish-German Gynecological Education and Research Foundation. Türkiye Bilimler Akademisi Acknowledgements: This work was funded by Turkish Academy of Sciences (TUBA). We would like to thank to Laboratory Technician Nurhayat Dönek from Bezmialem University for help throughout this research.

Accepted manuscript version. Published version available in Cancer Prevention Research, September 1 2017 (10) (9) 525-534 Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case–control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1,976 incident invasive breast cancer cases [estrogen receptor positive (ER+), n = 1,598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (Phet = 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01–1.63); Ptrend = 0.20], but not ER− disease. For both ER+ and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER−PR− disease [5th vs. 1st quintile RR = 0.60 (0.31–1.14); Ptrend = 0.03]. This study provides the first large-scale prospective data on circulating sRANKL and breast cancer. We observed limited evidence for an association between sRANKL and breast cancer risk.

Introduction Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups. Methods Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0–12.0 g/dL)/upper (10.5–13.0 g/dL)], gender (female/male), age (

Stimulation of erythropoiesis by the third-generation erythropoietin drug, continuous erythropoietin receptor activator (CERA), a pegylated derivative of epoetin-β, has provided valuable therapeutic benefits to patients suffering from renal anemia, but has also rapidly found application as an illicit performance-enhancing strategy in endurance sports. We present here a novel method for selective determination of CERA in serum, based on polyethylene glycol precipitation, followed by a commercial homogeneous immunoassay. The developed method was highly discriminating between serum samples from CERA-treated patients and control subjects, as the covalently linked polyethylene glycol chain in CERA strongly enhanced the solubility of the protein in a polyethylene glycol-containing medium. Intravenous administration of CERA could be detected for several weeks in the majority of subjects tested. This assay outperforms the currently available CERA detection methods in terms of simplicity, convenience, cost, and throughput, making it ideal as a screening tool for doping control.

Postmenopausal osteoporosis (PO) is a major public health issue which affects a large fraction of elderly women. Emergingin vitroevidence suggests a central role of oxidative stress (OxS) in postmenopausal osteoporosis (PO) development. Contrariwise, the human studies on this topic are still scarce and inconclusive. In the attempt to address this issue, we sought to determine if OxS, as assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG), may influence the level of receptor activator of nuclear factor-κb ligand (RANKL)/osteoprotegerin (OPG) ratio (a central regulator of bone metabolism) in a samplen=124, including postmenopausal women with osteoporosis, osteopenia and normal bone mass density (BMD). The most striking result that emerged in our study was the independent and positive (beta = 0.449,p=0.004, andR2=0.185) association between the OxS marker and RANKL/OPG ratio which was found in osteopenic but not in the other 2 sample groups. If confirmed by longitudinal studies, our findings would suggest that OxS is implicated in the derangement of bone homeostasis which precedes PO development. In line with these considerations, antioxidant treatment of postmenopausal women with moderately low BMD might contribute to preventing PO and related complications.

We hypothesised that tumour necrosis factor-α(TNF-α) may enhance receptor activator of nuclear factor-κβligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and culturedin vitroon plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α(anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p>0.05), there was a significant increase in the area of resorption on the surface (p<0.01) and under the surface (p<0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-αresulted in a significant reduction in the area of resorption on the surface (p<0.05) and under the surface (p<0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-αmodulates RANKL-mediated osteoclastic resorptionin vitroin patients with acute Charcot osteoarthropathy.

Copyright: © 2015 Perpétuo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited, Introduction: Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients. Methods: 13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed. Results: RANKL+ circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline. Conclusion: In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli., This work was supported by Fundação para a Ciência e Tecnologia (http://www.fct.pt/index.phtml.en) PhD grant (SFRH/BD/70533/2010) and in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp (http://www.merck.com/index.html - Merck_P08574). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.

Introduction: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor kappa B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA. Methods: 1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied. Results: We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value

Background Adalimumab blocks the action of tumor necrosis factor-alpha and reduces disease progression in rheumatoid arthritis and psoriatic arthritis. The effects of adalimumab in controlling progression of structural damage in erosive hand osteoarthritis (HOA) were assessed. Methods Sixty patients with erosive HOA on radiology received 40 mg adalimumab or placebo subcutaneously every two weeks during a 12-month randomized double-blind trial. Response was defined as the reduction in progression of structural damage according to the categorical anatomic phase scoring system. Furthermore, subchondral bone, bone plate erosion, and joint-space narrowing were scored according to the continuous Ghent University Score System (GUSS (TM)). Results The disease appeared to be active since 40.0% and 26,7% of patients out of the placebo and adalimumab group, respectively, showed at least one new interphalangeal (IP) joint that became erosive during the 12 months follow-up. These differences were not significant and the overall results showed no effect of adalimumab. Risk factors for progression were then identified and the presence of palpable soft tissue swelling at baseline was recognized as the strongest predictor for erosive progression. In this subpopulation at risk, statistically significant less erosive evolution on the radiological image (3.7%) was seen in the adalimumab treated group compared to the placebo group (14.5%) (P = 0.009). GUSSTM scoring confirmed a less rapid rate of mean increase in the erosion scores during the first 6 months of treatment in patients in adalimumab-treated patients. Conclusion Palpable soft tissue swelling in IP joints in patients with erosive HOA is a strong predictor for erosive progression. In these joints adalimumab significantly halted the progression of joint damage compared to placebo.