Serum Sclerostin Research Articles

Склеростин-залежні механізми формування остеопорозу у хворих цукровим діабетом 2 типу та ожирінням

при обстеженні 103 пацієнтів на цукровий діабет 2 типу (ЦД), що у 83 випадкахперебігав на тлі збільшеної маси тіла або ожиріння, було встановлено вірогідне збільшеннявмісту склеростину у сироватці крові, яке мало пряму кореляційну залежність з індексоммаси тіла. Висловлено припущення, що зміни даного глікопротеїну, який входить до групиантагоністів кісткових морфогенетичних білків, відбуваються внаслідок багатьох процесів ворганізмі: збільшення синтезу ФНП-α адипоцитами, ендотелієм судин, клітинами нейроглії натлі пре- та менопаузи, що сприяє порушенню мінеральної щільності кісткової тканини, тобтоформуванню остеопорозу. Ендокринний остеопороз становить найбільшу групу вторинногоостеопорозу, провідною причиною якого є цукровий діабет 2 типу. В разі наявності ЦД 2 типу,який перебігає на тлі ожиріння, формуються умови до розвитку остеопоротичних станів, одниміз механізмів розвитку яких може виступати глікопротеїн склеростин. Метою дослідженнястало визначення структурно-функціонального стану кісткової тканини шляхом дослідженнявмісту склеростину у хворих на цукровий діабет 2 типу, що перебігає на тлі топографічнихособливостей розподілу жирової тканини. До роботи було залучено 103 хворих на ЦД 2 типу,який у 83 випадках перебігав в поєднанні з надлишковою вагою або ожирінням (основна група). Догрупи порівняння увійшло 20 хворих на ЦД 2 типу, що був діагностований у пацієнтів з незмінениміндексом маси тіла (ІМТ). Вік хворих коливався від 31 до 55 років та в середньому по групах складав43±4,6 років та 44,1±2,1 роки відповідно. В обох групах хворих переважали чоловіки 44 (53%) та11 (55%) осіб. Тривалість захворювання реєструвалась в межах від 1 до 13 років. Визначеннярозподілу жирової тканини в організмі досліджували за допомогою ваг для характеристикискладу тіла - OMRON BF511 (Японія). Ідентифікували вміст вісцеральної жирової тканини(ВЖТ) та підшкірної жирової тканини (ПЖТ). Активність склеростину в сироватці крові
 визначали імуноферментним методом з використанням комерційних тест-систем «Biomedi-ca» (США) згідно інструкції на імуноферментному аналізаторі «Labline-90» (Австрія). Обробку
 отриманих даних здійснювали методом варіаційної статистики за допомогою ліцензійногопрограмного забезпечення Stata 10 («StatSoft Inc.», США). Перевірка на нормальність розподілуданих виконувалася за допомогою критерію Шапіро-Уілка. Для параметрів з нормальнимрозподілом розраховували середню величину (M) ± стандартну помилку середньої (m). Отриманірезультати розглядалися як статистично значущі при p<0,05. В результаті було визначено, щозбільшення ІМТ супроводжувалось підвищенням показника склеростину. Тобто, виявлені зміниглікопротеїну, який входить до групи антагоністів кісткових морфогенетичних білків, дають змогу припустити порушення процесу диференціації остеобластів. Тобто, як ЦД 2 типу, такі кількісна зміна жирової тканини з її перерозподілом, негативно впливають на метаболізмкісткової тканини. Так, перебіг цукрового діабету супроводжується збільшенням активностіпрозапальних цитокінів, а саме, ФНП-α – складового цитокінового каскаду жирової тканини.Цей феномен також пов’язують із залученням до процесу судин (ендотеліальні клітинипродукують даний цитокін), нервової тканини (залучення клітин нейроглії) та метаболічнимизсувами в організмі. Окрім того F.Xu та співавт. в експерименті доведено, що остеокластогенезпригнічується при гіперглікемічних та гіперінсулінемічних станах. Тобто, у хворих на ЦД призбільшенні ІМТ складається негативний «тандем» через додаткове надходження з багатьохклітин ФНП-α та збільшення синтезу склеростину, що не тільки «запускає» процес порушеннямінеральної щільності кісткової тканини (МЩКТ), але й підтримує його впродовж всьогоперебігу захворювання. Також певна роль відводиться віковому аспекту обстежених хворихна ЦД (середній вік менопаузи у здорових жінок нашої країни становить 45 років), що такожсприяє пригніченню кісткового метаболізму. В такому разі збільшення активності склеростинув поєднанні з негативним фоном (ожиріння, період менопаузи) можна розглядати як один ізмеханізмів формування остеопоротичних змін. При цьому поєднуються механізми первинного тавторинного ОП, що посилює і прискорює процес порушення архітектоніки кістки. Тому можназробити висновки, що у хворих на цукровий діабет 2 типу у поєднанні з ожирінням виникаютьумови до зниження якості кісткової тканини через уповільнення кісткового метаболізму, щосприяє формуванню остеопоротичних станів.

The Diagnostic Significance of Serum Sclerostin in Early Detection of Rheumatoid Arthritis in Syrian Patients

Background: Rheumatoid arthritis (RA) is associated with joint deformities and local bone erosions. Sclerostin is an inhibitor of the Wnt pathway and drives to reduce bone formation. Aims: Our study aimed to compare the diagnostic significance of sclerostin with anti-CCP (anti-cyclic citrullinated peptide; normal level<20 IU/ml, and rheumatoid factor (RF; normal level<16 IU/ml) for the early diagnosis of rheumatoid arthritis in Syrian patients. Methods: This study contained fifty-eight RA patients and thirty healthy individuals who were equally age- and sex-matched. Serum sclerostin and serum anti-CCP (IgG) levels were evaluated by using the enzyme-linked immunosorbent assay (ELISA). RA activity was assessed based on disease activity scores (DAS28). Results: Our results indicated that serum levels of sclerostin levels were higher in the RA group than in the healthy group (p<0.001). There was a positive correlation between serum sclerostin and DAS28-ESR (r=0.413, p=0.001). By ROC curve, the most optimal cut-off value of sclerostin was 249.69 pg/ml (AUC was 0.910 with 95% confidence interval (CI) values (0.852-0.969), sensitivity of 87.9%, and specificity of 93.3%) [Odds Ratio (OR) and P-value: 102, P< 0.0001]. In RA patients, the sensitivity and specificity of anti-CCP were 74.1% and 90%, and 70.6% and 86.6% of RF, respectively. Conclusion: Increased serum sclerostin may aid as a new prognostic biomarker for evaluating the activity of RA. Sclerostin showed higher sensitivity and specificity than anti-CCP and RF-IgM antibodies. Therefore, sclerostin is a sensitive and specific biomarker for early diagnosis of rheumatoid arthritis.

A pilot study: effect of irisin on trabecular bone in a streptozotocin-induced animal model of type 1 diabetic osteopathy utilizing a micro-CT.

Osteoporosis is a significant co-morbidity of type 1 diabetes mellitus (DM1) leading to increased fracture risk. Exercise-induced hormone 'irisin' in low dosage has been shown to have a beneficial effect on bone metabolism by increasing osteoblast differentiation and reducing osteoclast maturation, and inhibiting apoptosis and inflammation. We investigated the role of irisin in treating diabetic osteopathy by observing its effect on trabecular bone. DM1 was induced by intraperitoneal injection of streptozotocin 60 mg/kg body weight. Irisin in low dosage (5 µg twice a week for 6 weeks I/P) was injected into half of the control and 4-week diabetic male Wistar rats. Animals were sacrificed six months after induction of diabetes. The trabecular bone in the femoral head and neck was analyzed using a micro-CT technique. Bone turnover markers were measured using ELISA, Western blot, and RT-PCR techniques. It was found that DM1 deteriorates the trabecular bone microstructure by increasing trabecular separation (Tb-Sp) and decreasing trabecular thickness (Tb-Th), bone volume fraction (BV/TV), and bone mineral density (BMD). Irisin treatment positively affects bone quality by increasing trabecular number p < 0.05 and improves the BMD, Tb-Sp, and BV/TV by 21-28%. The deterioration in bone microarchitecture is mainly attributed to decreased bone formation observed as low osteocalcin and high sclerostin levels in diabetic bone samples p < 0.001. The irisin treatment significantly suppressed the serum and bone sclerostin levels p < 0.001, increased the serum CTX1 levels p < 0.05, and also showed non-significant improvement in osteocalcin levels. This is the first pilot study to our knowledge that shows that a low dose of irisin marginally improves the trabecular bone in DM1 and is an effective peptide in reducing sclerostin levels.

Sclerostin, Osteocytes, and Wnt Signaling in Pediatric Renal Osteodystrophy.

The pathophysiology of chronic kidney disease-mineral and bone disorder (CKD-MBD) is not well understood. Specific factors secreted by osteocytes are elevated in the serum of adults and pediatric patients with CKD-MBD, including FGF-23 and sclerostin, a known inhibitor of the Wnt signaling pathway. The molecular mechanisms that promote bone disease during the progression of CKD are incompletely understood. In this study, we performed a cross-sectional analysis of 87 pediatric patients with pre-dialysis CKD and post-dialysis (CKD 5D). We assessed the associations between serum and bone sclerostin levels and biomarkers of bone turnover and bone histomorphometry. We report that serum sclerostin levels were elevated in both early and late CKD. Higher circulating and bone sclerostin levels were associated with histomorphometric parameters of bone turnover and mineralization. Immunofluorescence analyses of bone biopsies evaluated osteocyte staining of antibodies towards the canonical Wnt target, β-catenin, in the phosphorylated (inhibited) or unphosphorylated (active) forms. Bone sclerostin was found to be colocalized with phosphorylated β-catenin, which suggests that Wnt signaling was inhibited. In patients with low serum sclerostin levels, increased unphosphorylated "active" β-catenin staining was observed in osteocytes. These data provide new mechanistic insight into the pathogenesis of CKD-MBD and suggest that sclerostin may offer a potential biomarker or therapeutic target in pediatric renal osteodystrophy.

Serum sclerostin level is positively associated with endothelial dysfunction measured by digital thermal monitoring in patients with type 2 diabetes: A prospective cross-sectional study.

Sclerostin and dickkopf-1 (DKK1), extracellular inhibitors of the canonical Wnt/β-catenin signaling pathway, have been associated with vascular aging and atherosclerosis. This study aimed to assess the correlation of sclerostin and DKK1 concentrations with endothelial function measured using vascular reactivity index (VRI) in patients with type 2 diabetes mellitus (T2DM). Fasting blood samples were collected from 100 patients with T2DM. Endothelial function and VRI were measured using digital thermal monitoring and circulating sclerostin and DKK1 levels by enzyme-linked immunosorbent assays. VRI values < 1.0, 1.0-1.9, and > 2.0 indicated poor, intermediate, and good vascular reactivity, respectively. Overall, 30, 38, and 32 patients had poor, intermediate, and good vascular reactivity, respectively. Older age, higher serum glycated hemoglobulin, urinary albumin-to-creatinine ratio, and sclerostin as well as lower hypertension prevalence, systolic blood pressure, and diastolic blood pressure (DBP) were associated with poor VRI. Multivariable forward stepwise linear regression analysis showed that DBP (β = 0.294, adjusted R2 change = 0.098, P < .001), log-glycated hemoglobin (β = -0.235, adjusted R2 change = 0.050, P = .002), log-urine albumin-to-creatinine ratio (β = -0.342, adjusted R2 change = 0.227, P < .001), and log-sclerostin level (β = -0.327, adjusted R2 change = 0.101, P < .001) were independently associated with VRI. Serum sclerostin, along with glycated hemoglobin and albumin-to-creatinine ratio, exhibited a negative correlation with VRI, while DBP showed a positive correlation with VRI. These factors can independently predict endothelial dysfunction in patients with T2DM.

Non-traditional HIIT-style ROTC training elicits positive bone quality and performance adaptations

ABSTRACT Military personnel experience elevated bone injury incidence, partly due to arduous and repetitive training. Non-traditional High-Intensity Interval Training-style (HIIT) may benefit pre-enlisted Reserve Officer Training Corps (ROTC) cadet’s musculoskeletal health and performance prior to military service. This study investigated 16 ROTC (n = 12 males; n = 4 females) and 15 physically active sex-, age-, and body mass-matched Controls’ musculoskeletal health and performance from November to April. Total body, lumbar spine, and dual- hip dual-energy X-ray absorptiometry scans and 4%, 38%, 66% tibial peripheral quantitative computed tomography scans, blood draws (serum sclerostin and parathyroid hormone), and maximal muscle strength and aerobic capacity testing were completed. From November to April, ROTC improved bone density (DXA) of the dominant total hip and greater trochanter and non-dominant greater trochanter and 38% and 66% tibial total volumetric and cortical bone density (pQCT) similarly or more than Controls (all p ≤ 0.049). From November to April, ROTC also improved bench and leg press, and peak aerobic capacity (all p ≤ 0.013). From November to January, serum sclerostin increased (p ≤ 0.007) and remained elevated through April, while parathyroid hormone was unchanged. HIIT-style training induced positive musculoskeletal adaptations, suggesting it may be an excellent pre-service training modality for this injury prone group.

Urinary Calcium Is Associated with Serum Sclerostin among Stone Formers.

Sclerostin plays an important role in bone metabolism and adipose tissue. Animal studies suggest that sclerostin influences urinary calcium (UCa), but this relationship has not been evaluated in stone formers (SFs). We aimed to investigate the association of UCa with serum sclerostin, bone mineral density (BMD), and body composition among SFs. Clinical and laboratorial data were retrieved from medical records. Determinants of UCa were studied using linear regression. A total of 107 SFs (35.8 ± 9.3 years, 54% male) with eGFR 99.8 ± 14.5 mL/min/1.73 were studied. Subjects were split by sex and grouped into tertiles of UCa levels. Men in the highest UCa tertile had higher body mass index (BMI) and serum sclerostin, lower lean mass, and a trend towards higher fat mass. Women in the highest tertile had higher BMI and a trend towards higher serum sclerostin. Hypertension and metabolic syndrome, but not lower BMD, were more prevalent in the highest UCa tertile for both sexes. Sclerostin was positively correlated with fat mass and inversely correlated with lean mass among men, but not among women. BMD corrected for BMI at lumbar spine was inversely associated with UCa in a univariate analysis, but only serum sclerostin, hypertension, and NaCl intake were independent determinants of UCa in the multivariate model. The present findings disclose that in addition to hypertension and salt intake, serum sclerostin is associated with urinary calcium in stone formers, suggesting that in addition to the hormones traditionally thought to alter calcium reabsorption in the kidney, sclerostin may play a significant additional role, warranting further investigation.

Effects of running a marathon on sclerostin and parathyroid hormone concentration in males aged over 50.

The aim of our study was to verify whether running a marathon (32nd Wroclaw Marathon) was associated with changes in sclerostin and intact PTH (iPTH) concentration in middle-aged males. We enrolled 33 males who completed the marathon race. Blood samples were taken 60 minutes before (V1), immediately after (V2), and 7 days after the run (V3). The mean serum sclerostin concentration was 42.4 ± 10.8 pmol/L at V1, increased to 62.9 ± 12.6 pmol/L at V2 (t= -11.206; p < 0.001) and returned to baseline in V3 (t = 8.344; p < 0.001, V3 vs. V2). A similar trend was recorded for iPTH (t= -7.440; p < 0.001, for V2 vs. V1; t = 6.229; p < 0.001, for V3 vs. V2), at V3, iPTH levels remained significantly higher than V1 (t= -2.759; p = 0.010). The results of our study suggest that, in middle-aged males, running a marathon affects skeletal metabolism by activating two counteracting mechanisms, although temporarily overlapping: first, by a sudden inhibition of bone formation, through induction sclerostin expression and, secondly, by a long-lasting induction of PTH, which also guarantees the maintenance of adequate circulating levels of calcium. The net effect would be the maintenance of adequately high levels of circulating calcium to be used for neuromuscular activity and muscle contraction.

Dynamics of Bone Disease Biomarkers Dickkopf-1 and Sclerostin in Patients with Multiple Myeloma.

Dickkopf-1 (DKK-1) and sclerostin are essential Wnt/β-catenin pathway inhibitors, playing an important role in multiple myeloma bone disease (MBD). We aimed to examine the serum DKK-1 and sclerostin variations in newly diagnosed multiple myeloma (NDMM) patients at diagnosis and in the course of therapy, including autologous stem cell transplantation (ASCT). This study included 41 NDMM-patients and 33 controls. MBD was assessed by whole-body low-dose computed tomography. DKK-1 and sclerostin were assayed by commercial ELISA kits. At diagnosis, NDMM-patients revealed significantly higher DKK-1 and sclerostin values (p < 0.0001), showing dependence on disease stage (lowest in ISS-I and highest in ISS-III: p < 0.0012 and p < 0.025, respectively, for both proteins). Bone lesions revealed significant positive correlation with both DKK-1 (p < 0.05) and sclerostin (p < 0.0001). In the course of therapy, significant reduction, more prominent after ASCT, was observed for both parameters in each treatment point compared to the baseline (p < 0.0001). Markedly lower sclerostin (p < 0.01) and DKK-1 (p < 0.05) values were observed in patients with complete and very good partial response compared to those with partial response, stable, or progressive disease. Sclerostin and DKK-1 in NDMM patients reflect the MBD severity and the effect of therapy. Both proteins could represent a novel tool for better disease monitoring and effectiveness of therapy.

Hyperbaric oxygen and treadmill exercise partially prevented bone loss and bone microarchitecture deterioration in ovariectomized rats.

Previous studies have demonstrated the beneficial effects of treadmill exercise (EX) on osteoporosis, and of hyperbaric oxygen (HBO) on osteoblast and osteoclast formation in vitro. We investigated the effects of HBO and the combination of HBO and EX on osteoporosis in ovariectomized rats. Forty 3-month-old female Sprague-Dawley rats were randomly divided into 5 groups (n = 8): a sham control group (Control); an ovariectomy group; an ovariectomy with treadmill exercise treatment group; an ovariectomy with HBO treatment group; and an ovariectomy with HBO treatment combined with treadmill exercise group. The HBO exposures were 203 kPa, 85-90% O₂, 90 min and the exercise regimen was 20 m·min⁻¹, 40 min·day¹, 5° slope. Both treatments were administered once daily, five days a week for 12 weeks until the rats were sacrificed. All three treatments (HBO, exercise, and both combined) significantly promoted the expression of the osteoblast-related gene and oxidative metabolism-related gene (PGC-1α). They also exerted significant inhibitory effects on the osteoclast-related mRNA expression (RANKL) and bone resorption marker CTX-I. Additionally, exercise and the combination exercise-HBO treatment increased serum superoxide dysmutase (SOD) and sclerostin expression. No significant between-group difference was observed. Hyperbaric oxygen, exercise, and the combination ameliorated bone microarchitecture deterioration and ovariectomy-induced bone loss in rats, and these inhibitory effects may be associated with the increased SOD and up-regulated PGC-1α.

Reactive oxygen species-mediated endoplasmic reticulum stress contributes to osteocyte death induced by orthodontic compressive force.

During orthodontic tooth movement (OTM), osteocytes, the most mechanosensitive cells in alveolar bone, suffer the heavy orthodontic force and initiate alveolar bone resorption on the compression side. However, the inherent mechanisms of compressive force-induced osteocyte death are not fully understood. In this study, we established an OTM model on Sprague-Dawley rats by inserting coil springs to investigate osteocyte damage on the compression side of alveolar bone. We then applied compressive force on the MLO-Y4 osteocyte-like cell line in vitro to explore whether the reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ERS) pathway is involved in compressive force-induced osteocyte death. We found that the orthodontic force caused apparent alveolar bone loss, osteocyte death, and elevated serum sclerostin and receptor activator of NF-κB ligand (RANKL) levels in rats. In vitro, compressive force inhibited cell viability but increased the LDH leakage and loss of mitochondrial membrane potential in MLO-Y4 cells. Simultaneously, it activated protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2 (eIF2α), and their downstream pro-apoptotic ERS signaling proteins and caused significant osteocyte apoptosis, which can be blocked by ERS inhibitor salubrinal. Moreover, the compressive force elevated intracellular ROS levels, while the ROS scavenger N-acetyl-L-cysteine (NAC) alleviated ERS and apoptosis in loaded osteocytes. These results suggest that the orthodontic compressive force induced osteocyte apoptosis via the ROS-mediated ERS pathway. This study first proposes the ERS pathway as a new potential pathway for regulating the rate of OTM based on osteocyte death. RESEARCH HIGHLIGHTS: The orthodontic force increases osteocyte death in rat alveolar bone. The compressive force causes osteocyte apoptosis by the endoplasmic reticulum stress (ERS) pathway in vitro. The ROS scavenger NAC blocked compressive force-induced ERS and osteocyte apoptosis.

Sclerostin decreases in regular swimmers after ice swimming and is associated with meteorin-like protein serum levels.

Introduction: Cold and exercise are two important stimuli affecting the secretion of osteokines and adipomyokines, which often occur simultaneously. However, few studies have investigated the changes in osteokines and adipomyokines induced by exercise during severe cold and their corresponding associations. Therefore, this study aimed to investigate the changes in sclerostin and meteorin-like (metrnl) protein before and after cold exercise (ice swimming [IS]) and observe their correlation. Methods: For this, 56 daily ice swimmers' data were included in this study. Serum sclerostin and metrnl were measured 30 min before IS and 30 min after. The fat mass, visceral fat area, fat-free mass, skeletal muscle mass, lumbar spine, and femoral neck bone mineral density of the ice swimmers were measured. Results: After IS, sclerostin exhibited significant decreases, whereas metrnl showed no significant change. In addition, the baseline level of sclerostin and the decrease in sclerostin were positively correlated with serum metrnl after adjusting for age, gender, and body composition indicators. Discussion: IS caused a significant decrease in sclerostin but did not affect metrnl. Furthermore, the associations between sclerostin and metrnl suggested a correlation between osteokines and adipomyokines; this encourages future exploration of the interconnection between bone, muscle, and fat, which will be beneficial for identifying potential common therapeutic targets for diseases such as osteoporosis, sarcopenia, and obesity.

#3069 CIRCULATING SCLEROSTIN AFFECTS URINARY CALCIUM EXCRETION AMONG STONE FORMERS

Abstract Background and Aims Sclerostin plays an important role in bone metabolism and adipose tissue. Experimental studies suggest that sclerostin also influences urinary calcium excretion (Uca), but this relationship has not been addressed in humans. We aimed to study the association of UCa levels with serum sclerostin, bone mineral density (BMD) and body composition among stone-formers (SF). Method We retrieved data from patient records, including clinical characteristics, nutritional, biochemistry and hormonal data as well as BMD and body composition determined by dual energy X-ray absorptiometry. Serum sclerostin levels were measured using ELISA kits. Determinants of UCa were studied using multivariate linear regression. Results A total of 107 SF (35.8 ± 9.3 years, 54% male) with eGFR of 99.8 ± 14.5 mL/min/1.73 were included. The subjects were divided by sex and clustered into tertiles according to UCa as shown in Table 1. Men in the highest UCa tertile had higher body mass index (BMI) and serum sclerostin levels, were more likely to have hypertension and metabolic syndrome, had lower lean mass, a trend towards higher fat mass (p = 0.06), and no statistical differences in BMD. Women in the highest UCa tertile had higher BMI and a trend towards higher serum sclerostin levels (p = 0.06), were more likely to have hypertension and metabolic syndrome, with no differences in BMD. Sclerostin was positively correlated with fat mass (r = 0.38, p = 0.004) and inversely correlated with lean mass (r = -0.32, p = 0.01) among men, but not among women. To further adjust for the influence of weight load on BMD for both sexes, the latter was also expressed as a ratio per BMI (BMD/BMI). Although lumbar spine BMD/BMI was inversely associated with UCa (β -0.26, p = 0.01) in univariate analysis, it lost significance in the multivariate model (Table 2). Hypertension, metabolic syndrome and serum sclerostin were independent determinants of UCa (Table 2). Conclusion Present findings disclosed that serum sclerostin, hypertension and metabolic syndrome were independent determinants of urinary calcium in stone formers. These data suggest that in addition to the hormones traditionally thought to alter calcium reabsorption in the kidney, sclerostin may play a significant additional role, warranting further intervention studies in order to test potential medication strategies to reduce calciuria in this population.

The role of sclerostin in the formation of cardiovascular calcifi cation in chronic kidney disease C5D

THE AIM: to study the relationship of blood sclerostin with clinical parameters and its influence on the probability of detection of cardiovascular calcification in patients with CKD C5D. PATIENTS AND METHODS. The study was a single-stage, cohort study involving 84 patients with stage 5D CKD who received hemodialysis therapy, including 40 (47.6 %) female patients and 44 (52.4 %) male patients. The average age was 55.6±14.9 years. The examination included, in addition to routine studies, echocardioscopy with an assessment of calcification of the heart valves, abdominal radiography in the lateral projection with an assessment of aortic calcification, analysis of indicators that characterize phosphorus-calcium metabolism (serum sclerostin levels, 1.25(OH)D, FGF-23, A-klotho, PTH, P and Cа blood). Statistical analysis was performed using the computer program STATISTICA 12.6 (StatSoft Inc., USA). RESULTS. It was shown that the level of sclerostin is higher in the elderly, as well as those who have signs of hypoproteinemia and hypoalbuminemia, indirectly indicating the presence of protein-energy deficiency. There is an Association of blood sclerostin with FGF-23 and Alpha-klotho. From the point of view of the probable influence on the processes of cardiovascular calcification, this relationship shows its unidirectionality. Increased blood sclerostin levels have been shown to be associated with the risk of detecting signs of cardiovascular calcification. Moreover, it is shown that the higher the level of sclerostin in the blood, the more pronounced the degree of this calcification. Along with the increase in the level of sclerostin, the ability of a deficit of 1.25(OH)D to lead to the development of calcification was confirmed. CONCLUSION. A high level of sclerostin in the blood serum of more than 92.5 pmol / l in patients with CKD C5D increases the risk of detecting signs of cardiovascular calcification (calcification of the aortic wall and heart valves). An increase in sclerostin levels occurs in conjunction with an increase in FGF-23 and a decrease in 1.25(OH)D

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

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

Peroxisome proliferator activated receptor-γ in osteoblasts controls bone formation and fat mass by regulating sclerostin expression

The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a key contributor to metabolic function via its adipogenic and insulin-sensitizing functions, but it has negative effects on skeletal homeostasis. Here, we questioned whether the skeletal and metabolic actions of PPARγ are linked. Ablating Pparg expression in osteoblasts and osteocytes produced a high bone mass phenotype, secondary to increased osteoblast activity, and a reduction in subcutaneous fat mass because of reduced fatty acid synthesis and increased fat oxidation. The skeletal and metabolic phenotypes in Pparg mutants proceed from the regulation of sclerostin production by PPARγ. Mutants exhibited reductions in skeletal Sost expression and serum sclerostin levels while increasing production normalized both phenotypes. Importantly, disrupting the production of sclerostin synergized with the insulin-sensitizing actions of a PPARγ agonist while preventingbone loss. These data suggest that modulating sclerostin action may prevent bone loss associated with anti-diabetic therapies and augment their metabolic actions.

Influence of Muscle Mass and Strength on Bone Mineralisation with Consideration of Sclerostin Concentration.

Osteoporosis is a disease characterised by a reduction in bone strength due to increased porosity and impaired mineralisation. In our study, we investigated whether muscle strength and mass exert a significant effect on bone mineral density in young adult women. We also tested whether sclerostin can be used as an indicator in the assessment of bone mineralisation. The study included 111 patients. All patients had their bone mineral density determined in the L1-L4 section of the lumbar spine and in the whole skeleton. The parameters of fat mass (FM), lean body mass (LBM) and visceral fat mass (VF) were also determined. Metabolic activity of osteocytes was assessed by measuring the serum sclerostin concentration. There was a statistically significant association of both hands' muscle strength with all parameters expressing bone mineralisation. A statistically significant relationship was also obtained between BMD L1-L4 and the body mass components (FM, LBM). Sclerostin levels in the study did not differ between groups with normal and reduced bone mineral density. Muscle strength assessment may be a potential exponent of reduced bone mineral density, also used clinically in young adult women. The utility of sclerostin in the clinical assessment of bone mineralisation has not been demonstrated.

Serum Osteocalcin, Sclerostin and Lipocalin-2 Levels in Adolescent Boys with Obesity over a 12-Week Sprint Interval Training.

The aim of the study was to examine the effects of supervised cycling sprint interval training (SIT) on serum osteocalcin, lipocalin-2 and sclerostin levels, and bone mineral characteristics among obese adolescent boys. Untrained obese adolescent boys aged 13.4 ± 0.3 were assigned to either a 12-week SIT group (3 sessions/week), or a non-exercising control group who continued with their habitual everyday life. Serum osteocalcin, lipocalin-2 and sclerostin concentrations, and bone mineral values were assessed before and after intervention. After 12-week intervention, where 14 boys in both groups ended the study, there were no significant differences in serum osteokine levels between the groups after 12 weeks, while whole body bone mineral content and lower limb bone mineral density increased in the SIT group (p < 0.05). Change in body mass index was negatively correlated with the change in osteocalcin (r = -0.57; p = 0.034), and positively correlated with the change in lipocalin-2 levels (r = 0.57; p = 0.035) in the SIT group. Supervised 12-week SIT intervention improved bone mineral characteristics, but did not change osteocalcin, lipocalin-2 or sclerostin levels in adolescent boys with obesity.

FGF-23 and sclerostin in serum and bone of CKD patients.

Renal osteodystrophy occurs in the early stages of chronic kidney disease (CKD) and progresses during loss of kidney function. Fibroblast growth factor (FGF)-23 and sclerostin, both produced by osteocytes, are increased in blood of patients with CKD. The aim of this study was to analyze the impact of decline in kidney function on FGF-23 and sclerostin protein expression in bone and to study their relationship with their serum levels and bone histomorphometry. 108 patients aged 25-81 years (mean ± SD: 56±13 years) underwent anterior iliac crest biopsies after double-tetracycline labeling. Eleven patients were CKD-2, 16 were CKD-3, 9 were CKD-4 - 5, and 64 CKD-5D. Patients were on hemodialysis for 49±117 months. 18 age-matched patients without CKD were included as controls. Immunostaining was performed on undecalcified bone sections to quantify FGF-23 and sclerostin expression. Bone sections were also evaluated by histomorphometry for bone turnover, mineralization, and volume. FGF-23 expression in bone correlated positively with CKD stages (p<0.001) increasing from 5.3- to 7.1-fold starting at CKD-2. No difference in FGF-23 expression was seen between trabecular and cortical bone. Sclerostin expression in bone correlated positively with CKD stages (p<0.001) with an increase from 3.8- to 5.1-fold starting at CKD-2. This increase was progressive and significantly greater in cortical than cancellous bone. FGF-23 and sclerostin in blood and bone were strongly associated with bone turnover parameters. Expression of FGF-23 in cortical bone correlated positively with activation frequency (Ac.f) and bone formation rate (BFR/BS) (p<0.05), while sclerostin correlated negatively with Ac.f, BFR/BS, and osteoblast and osteoclast numbers (p<0.05). FGF-23 trabecular and cortical expressions correlated positively with cortical thickness (p<0.001). Sclerostin bone expression correlated negatively with parameters of trabecular thickness and osteoid surface (p<0.05). These data show a progressive increase in FGF-23 and sclerostin in blood and bone associated with decrease in kidney function. The observed relationships between bone turnover and sclerostin or FGF-23 should be considered when treatment modalities are developed for management of turnover abnormalities in CKD patients.

Mild Chronic Kidney Disease Associated with Low Bone Formation and Decrease in Phosphate Transporters and Signaling Pathways Gene Expression.

The initial phases of molecular and cellular maladaptive bone responses in early chronic kidney disease (CKD) remain mostly unknown. We induced mild CKD in spontaneously hypertensive rats (SHR) by either causing arterial hypertension lasting six months (sham-operated rats, SO6) or in its' combination with 3/4 nephrectomy lasting two and six months (Nx2 and Nx6, respectively). Sham-operated SHRs (SO2) and Wistar Kyoto rats (WKY2) with a two-month follow-up served as controls. Animals were fed standard chow containing 0.6% phosphate. Upon follow-up completion in each animal, we measured creatinine clearance, urine albumin-to-creatinine ratio, renal interstitial fibrosis, inorganic phosphate (Pi) exchange, intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1, sclerostin, and assessed bone response by static histomorphometry and gene expression profiles. The mild CKD groups had no increase in renal Pi excretion, FGF23, or PTH levels. Serum Pi, Dickkopf-1, and sclerostin were higher in Nx6. A decrease in trabecular bone area and osteocyte number was obvious in SO6. Nx2 and Nx6 had additionally lower osteoblast numbers. The decline in eroded perimeter, a resorption index, was only apparent in Nx6. Significant downregulation of genes related to Pi transport, MAPK, WNT, and BMP signaling accompanied histological alterations in Nx2 and Nx6. We found an association between mild CKD and histological and molecular features suggesting lower bone turnover, which occurred at normal levels of systemic Pi-regulating factors.