Sclerostin Levels Research Articles

Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes.

Sclerostin inhibitors protect against osteoporotic fractures, but their cardiovascular safety remains unclear. We conducted a cis-Mendelian randomisation analysis to estimate the causal effect of sclerostin levels on cardiovascular risk factors. We meta-analysed three GWAS of sclerostin levels including 49,568 Europeans and selected 2 SNPs to be used as instruments. We included heel bone mineral density and hip fracture risk as positive control outcomes. Public GWAS and UK Biobank patient-level data were used for the study outcomes, which include cardiovascular events, risk factors, and biomarkers. Lower sclerostin levels were associated with higher bone mineral density and 85% reduction in hip fracture risk. However, genetically predicted lower sclerostin levels led to 25-85% excess coronary artery disease risk, 40% to 60% increased risk of type 2 diabetes, and worse cardiovascular biomarkers values, including higher triglycerides, and decreased HDL cholesterol levels. Results also suggest a potential (but borderline) association with increased risk of myocardial infarction. Our study provides genetic evidence of a causal relationship between reduced levels of sclerostin and improved bone health and fracture protection, but increased risk of cardiovascular events and risk factors.

Association of lower serum sclerostin levels with elevated risk for increased arterial stiffness: The JPOS Cohort Study.

Studies on the relationship between serum sclerostin, a Wnt/β-catenin pathway inhibitor, and atherosclerosis have yielded inconsistent results. We aim to longitudinally investigate the relationship between serum sclerostin levels and the risk of increased arterial stiffness in Japanese community-dwelling women. Of 1044 women aged ≥50 years whose brachial-ankle pulse wave velocity (baPWV) value was available in a baseline survey in 2011-2012, we excluded 374 whose baPWVs were ≥1800 cm/s, set as the cutoff for increased arterial stiffness, and eight with missing data. Of the remaining 662 women, we included in the analysis 556 followed in the 4- to 5-year follow-up study. The coefficient of variation of the sclerostin measurement was 3.45%. We obtained odds ratios (ORs) for sclerostin at baseline categorized by tertiles, with the high tertile as reference for increased arterial stiffness. Ninety-four women showed increased arterial stiffness during a mean follow-up of 4.0 years. The increased arterial stiffness rates in the low, medium, and high tertiles were 22.2%, 16.1%, and 12.4%, respectively (trend test p = 0.013). The ORs for the medium and low tertiles for increased arterial stiffness were 1.58 (p = 0.205) and 2.16 (p = 0.027), respectively, after adjusting for age and baseline baPWV. After further adjustment for baseline BMI, hypertension, hyperlipidemia, diabetes mellitus, eGFR, and BMC at whole body, the ORs for the medium and low tertiles were 1.65 (p = 0.181) and 2.50 (p = 0.014), respectively. Lower serum sclerostin levels were associated with elevated risks for increased arterial stiffness in Japanese community-dwelling women.

Glycogen Storage Disease Type I and Bone: Clinical and Cellular Characterization.

Glycogen storage disease (GSD) is the most prevalent inherited disorder of glycogen metabolism for which no causal treatment is available. In recent years, thanks to the improved clinical management, the life expectancy of these patients extended, disclosing previously unidentified adverse conditions in other organs. In this study, we evaluated the clinical bone complications and the cellular responses in 20 patients (aged 14.1 ± 3.4years) affected by GSD type I. Fragility fractures were reported in 35% of the patients, which were older than unfractured patients. They involved appendicular skeletal segments, while no vertebral deformity was detected. 60% of the patients had a bone mineral density (BMD) "below the expected range for age", and lumbar spine (LS) BMD Z-scores positively correlated with muscle strength. Circulating mineral and bone markers showed reduction in the older subjects, with no increase in the pubertal age. Significant correlations could not be detected between circulating markers and LS BMD Z-scores, except for sclerostin levels, which also correlated with muscle strength. The osteoclasts differentiated from patients' peripheral blood mononuclear cells did not show cell-autonomous alterations. However, circulating osteoclast precursors from healthy individuals cultured in the presence of patients' sera exhibited increased osteoclastogenesis compared to control sera suggesting that GSD type I serum factors could affect osteoclast function in a non-autonomous manner. In contrast, circulating osteoprogenitors were unremarkable.

Elevated Circulating Sclerostin Levels in Frail Older Adults: Implications beyond Bone Health.

Sclerostin, initially recognized for its pivotal role in bone metabolism, has gained attention for its multifaceted impact on overall human health. However, its influence on frailty-a condition that best reflects biological age-has not been thoroughly investigated. We collected blood samples from 244 older adults who underwent comprehensive geriatric assessments. Sclerostin levels were quantified using an enzyme-linked immunosorbent assay. Frailty was assessed using two validated approaches: the phenotypic model by Fried and the deficit accumulation frailty index (FI) by Rockwood. After controlling for sex, age, and body mass index, we found that serum sclerostin levels were significantly elevated in frail individuals compared to their robust counterparts (P<0.001). There was a positive correlation between serum sclerostin concentrations and the FI (P<0.001). Each standard deviation increase in serum sclerostin was associated with an odds ratio of 1.87 for frailty (P=0.003). Moreover, participants in the highest quartile of sclerostin levels had a significantly higher FI and a 9.91-fold increased odds of frailty compared to those in the lowest quartile (P=0.003 and P=0.039, respectively). These findings, which for the first time explore the association between circulating sclerostin levels and frailty, have significant clinical implications, positioning sclerostin as one of potential blood-based biomarkers for frailty that captures the comprehensive physical, mental, and social aspects of the elderly, extending beyond its traditional role in bone metabolism.

Assessment of trabecular bone score using updated TBSTT in anorexia nervosa-The AN-BO study.

Anorexia Nervosa (AN) is characterized by a distortion of body image, very low body weight, malnutrition and hormonal dysregulations, resulting in reduced bone mineral density (BMD) and impaired bone microarchitecture. The updated Trabecular Bone Score (TBS) algorithm accounts for soft tissue thickness (TBSTT) instead of BMI (TBSBMI). The aim of the study was to assess both TBS algorithms in adult AN patients compared to normal-weight controls(CTRL). This retrospective cross-sectional study investigated 34 adult female anorexia nervosa (AN) patients and 26 healthy normal-weighted age- and sex-matched controls (CTRL). Bone texture analysis was assessed by TBSTT and TBSBMI (TBS iNsight® V4.0 and V3.1), bone mineral density (BMD; lumbar spine LS, femoral neck, total hip) and body composition by DXA (GE Lunar iDXATM). Laboratory analyses included bone turnover markers (CTX; P1NP; sclerostin). Data analysis was performed using parametric (t-test) or non-parametric test (Mann-Whitney-U-Test) depending on normality, one-way ANCOVA and correlation analysis (Perason's or Spearman's). AN patients (BMI 14.7(1.6)) and CTRL (BMI 22.4(4.0)) were of comparable age (22.8(7.1) vs.25.0(4.0)years, p = 0.145). TBSTT(1.319±0.09 vs.1.502±0.07, p<0.001) and TBSBMI(1.317±0.10 vs.1.548±0.09, p<0.001) were significantly lower in AN patients compared to CTRL. Soft tissue thickness was lower in AN (p<0.001). Within the CTRL group, but not in AN, TBSTT and TBSBMI were significantly different (p<0.001). BMD was lower at all sites in AN patients (p<0.001 for all), being lowest at LS. Bone Mineral Content, Lean Body mass and Fat Mass were lower in AN (p<0.001). AN patients had lower P1NP (p = 0.05), but higher CTX (p = 0.001) and sclerostin (p = 0.003) levels. Adult AN patients have lower TBSTT and TBSBMI, reduced BMD and an uncoupling of bone turnover. In AN both TBS algorithms show similar reduced trabecular bone microarchitecture. The observed difference of TBSTT and TBSBMI in CTRL with normal body composition highlight the importance of the new algorithm.

Subclinical carotid atherosclerosis in gouty patients: relation to musculoskeletal ultrasonographic findings and serum sclerostin level

Objectives. To detect subclinical carotid atherosclerosis in gout patients and its relation to musculoskeletal ultrasound (MSK US) manifestations and serum sclerostin (SCL) levels. Patients and methods. Thirty Egyptian gouty patients were classified into two groups: Group A included 15 patients with diagnostic MSK US manifestations of gout (double contour sign), and Group B included 15 patients without MSK US findings. MSK US was done for both knees and the first MTP joints. Carotid duplex ultrasonography was done to evaluate carotid intima-media-thickness (CIMT) and serum SCL level was measured in all patients by ELISA technique. Results. Gouty patients with MSK US findings had a significantly higher increase in serum SCL levels than those without MSK US findings (p &lt;0.01). Group A patients had a significantly greater CIMT than patients of group B (p &lt;0.01). Serum uric acid and SCL levels were found to be significantly positively correlated. The ROC curve revealed that the optimal SCL cutoff value for detecting positive MSK US findings in gout patients was &gt;25.05 ng/ml. At this level, there was a significant difference between the patients with a CIMT &gt;0.9 mm and the patients with a CIMT ≤0.9 mm (p &lt;0.05). Conclusions. Patients with MSK US manifestations of gout are more liable to have subclinical carotid atherosclerosis than patients without these manifestations. SCL at a certain level &gt;25.05 ng/ml in gout patients might predispose patients to radiographic findings of MSK US of gout and subclinical atherosclerosis.

SOST/Sclerostin impairs the osteogenesis and angiogesis in glucocorticoid-associated osteonecrosis of femoral head.

Glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH) is a progressive bone disorder which frequently results in femoral head collapse and hip joint dysfunction. Sclerostin (SOST) is principally secreted by osteocytes in bone and plays an important role in bone homeostasis and homeostasis of skeletal integrity. Our previous study reported that short-term use of glucocorticoid increased serum sclerostin levels. Here this study is aimed to identify whether sclerostin played an essential role in the occurrence and development of GA-ONFH. Glucocorticoid-induced osteonecrosis of femoral head (ARCO stage II) samples were collected and sclerostin staining was conducted. Osteocyte cell line Ocy454, MC3T3-E1 and endothelial cells was used. MC3T3-E1 or endothelial cells were co-cultured with Ocy454 or SOST-silencing Ocy454 in presence of dexamethasone to mimic the crosstalk of various cells in the bone niche. GA-ONFH rat model and SOST knockout model was built to better understand the phenomenon in vivo. Sclerostin was highly concentrated in osteonecrosis patient sample in the necrotic area. Co-culture with osteocytes aggravated the inhibition of dexamethasone on MC3T3-E1 and endothelial cells. Sclerostin derived from osteocytes impaired osteogenesis and angiogenesis via inhibiting the Wnt pathway. In GA-ONFH rat model, SOST knockout ameliorated the incidence of osteonecrosis and improved bone metabolism compared with the wild type group through histological, immunohistochemical and bone metabolic analyses. Sclerostin contribute to pathologic process of GA-ONFH by impairing osteogenesis and angiogenesis.

Relation between serum sclerostin and CTRP3 levels and bone mineral density in diabetic postmenopausal women

BackgroundOsteoporosis (OP) is a common finding in diabetic patients especially high-risk populations such as postmenopausal women. Sclerostin is a glycoprotein chiefly secreted by mature osteocytes and is considered a main regulator of bone formation. The C1q/TNF-Related Protein 3 (CTRP3) was found to be significantly associated with OP in postmenopausal women. The effect of type 2 diabetes mellitus (T2DM) on sclerostin and CTRP3 levels in postmenopausal women is rarely investigated. The present study aimed to assess the impact of T2DM on sclerostin and CTRP3 levels and their relation to OP in postmenopausal women.MethodsThe study included 60 postmenopausal women with T2DM and 60 age-matched postmenopausal non-diabetic women. Bone mineral density (BMD) was assessed using dual energy X-ray absorptiometry (DEXA). Serum levels of sclerostin and CTRP3 were assessed using enzyme-linked immunosorbent assay (ELISA) technique.ResultsDiabetic group expressed significantly higher serum levels of sclerostin when compared with non-diabetic group (110.0 ± 29.0 versus 51.5 ± 23.2 ng; p < 0.001). Oppositely, CTRP3 were significantly lower in the diabetic group (3.5 ± 3.5 versus 9.9 ± 3.7 ng/ml, p < 0.001). Multivariate logistic regression analysis identified HbA1c levels [OR (95% CI): 0.49 (0.26–0.93), p = 0.028], sclerotin levels [OR (95% CI): 1.06 (1.0-1.012), p = 0.041] and CTRP3 levels [OR (95%) CI: 1.64 (1.0-2.68), p = 0.047] as significant predictors of OP in diabetic patients.ConclusionsSclerostin and CTRP3 levels are involved in OP in postmenopausal diabetic patients.

α-Klotho is associated with cardiovascular and all-cause mortality in patients with stage3band 4 chronic kidney disease(CKD): a long-term prospective cohort study.

α-Klotho deficiency may increase cardiovascular risks and worsen survival. We evaluated the association of α-Klotho with cardiovascular and all-cause mortality in pre-dialysis chronic kidney disease (CKD) patients. In this prospective study, 75 non-diabetic CKD stage 3b-4 patients werefollowed-up for a median of 8years. Primary and secondary outcomes were all-cause and cardiovascular mortality, respectively. Human soluble α-Klotho ELISA Assay (IBL-Takara 27,998-96Well), Human Fibroblast Growth Factor-23 ELISA Assay (intact FGF23, Merck Millipore MILLENZ FGF23-32K), and Human Sclerostin ELISA kits (Biomedica, Vienna, BI-20492) were used to measure serum α-Klotho, FGF23 and sclerostin levels in the certified laboratory at the Sechenov University according to the manufacturers' protocols.All patients underwent echocardiography to evaluate left ventricular mass index (LVMI), left ventricular ejection fraction by Simpson method, and cardiac (valve) calcification score by a semi-quantitative point scale. Lateral abdominal radiography by Kauppila method was used to estimate calcificationof the abdominal aorta.Cox multivariate regression and receiver-operating characteristic curve (ROC)-analysis were used to evaluate risk factors for death and their cut-off values. Primary and secondary endpoints were reached in 15 (20%) and 9 (12%) patients, respectively. Median α-Klotho levels in deceased and surviving patients were 344 and 484pg/ml, respectively (p = 0.002). In a multivariate Cox regression model, baseline α-Klotho levels (HR 0.99, 95% CI 0.98-1.00, p = 0.023), aortic calcification (HR 1.18, 95% CI 1.02-1.36, p = 0.029) and left ventricular mass index (LVMI) (HR 1.04, 95% CI 1.00-1.08, p = 0.033) were associated with the primary endpoint, whereas α-Klotho (HR 0.99, 95% CI 0.98-1.00, p = 0.029), aortic calcification (HR 1.23, 95% CI 1.07-1.42, p = 0.003) and LVMI (HR 1.04, 95% CI 1.00-1.08, p = 0.021) were associated with the secondary endpoint. α-Klotho levels had the highest area under the curve (AUC)by ROC analysis, that is, 0.766 (95% CI 0.70-0.82) for the primary endpoint and 0.842 (95% CI 0.79-0.90) for the secondary endpoint with cut-off values of 412pg/ml (HR 3.06, 95% CI 1.36-6.89, p = 0.007) and 368pg/ml (HR 4.84, 95% CI 1.59-14.73, p = 0.005), respectively. In pre-dialysis CKD patients, α-Klotho levels areassociated with all-cause and cardiovascular mortality and may be considered an early prognostic marker.

Bone proteins are associated with cardiovascular risk according to the SCORE2-Diabetes algorithm

BackgroundTypical bone proteins, such as sclerostin and periostin, have been associated with cardiovascular disease (CVD). Simultaneously, several risk scores have been developed to predict CVD in the general population. Therefore, we aimed to evaluate the association of these bone proteins related to CVD, with the main vascular risk scales: Framingham Risk Score (FRS), REGICOR and SCORE2-Diabetes, in patients with type 2 diabetes. We focus in particular on the SCORE2-Diabetes algorithm, which predicts 10-year CVD risk and is specific to the study population.MethodsThis was a cross-sectional study including 104 patients with type 2 diabetes (62 ± 6 years, 60% males). Clinical data, biochemical measurements, and serum bioactive sclerostin and periostin levels were collected, and different risk scales were calculated. The association between bioactive sclerostin or periostin with the risk scales was analyzed.ResultsA positive correlation was observed between circulating levels of bioactive sclerostin (p < 0.001) and periostin (p < 0.001) with SCORE2-Diabetes values. However, no correlation was found with FRS or REGICOR scales. Both serum bioactive sclerostin and periostin levels were significantly elevated in patients at high-very high risk of CVD (score ≥ 10%) than in the low-moderate risk group (score < 10%) (p < 0.001 for both). Moreover, analyzing these proteins to identify patients with type 2 diabetes at high-very high vascular risk using ROC curves, we observed significant AUC values for bioactive sclerostin (AUC = 0.696; p = 0.001), periostin (AUC = 0.749; p < 0.001), and the model combining both (AUC = 0.795; p < 0.001). For diagnosing high-very high vascular risk, serum bioactive sclerostin levels > 131 pmol/L showed 51.6% sensitivity and 78.6% specificity. Similarly, serum periostin levels > 1144 pmol/L had 64.5% sensitivity and 76.2% specificity.ConclusionsSclerostin and periostin are associated with vascular risk in the SCORE2-Diabetes algorithm, opening a new line of investigation to identify novel biomarkers of cardiovascular risk in the type 2 diabetes population.Graphical

Correlation between Body Composition and Bone Mineral Density Differs by Sex and Skeletal Site in Overweight and Obese Chinese Subjects

Previous studies have yielded inconsistent results regarding the relationship between obesity and bone mineral density (BMD). The aim of this study was to determine the influence of body composition on BMD and the serum sclerostin level in overweight and obese adults. The study had a cross-sectional design and included 90 men and 118 women with a body mass index ≥25. Fat mass, lean mass, and spinal and pelvic BMD were measured using dual-emission X-ray absorptiometry. Subcutaneous fat, visceral fat, and lean mass were measured between L2 and L3 by 16-slice spiral computed tomography. The serum sclerostin level was determined by enzyme-linked immunosorbent assay. Pearson analysis showed that fat mass and appendicular lean mass were positively correlated with spinal BMD in both sexes. A positive association of both fat mass and lean mass with pelvic BMD, which was stronger in women, was also found. Partial correlation analysis showed the positive association between fat mass and BMD was significantly attenuated but the positive association between lean mass and pelvic BMD remained after adjustment for age and body weight. A negative correlation was observed between visceral fat and spinal and pelvic BMD only in women, and the positive association between lean mass with pelvic BMD was more obvious in women than in men, indicating body composition seemed to have a greater impact on the BMD in women. The serum sclerostin level was positively associated with BMD but not with body composition. These findings suggest that the correlation between body composition and BMD is influenced by sex and skeletal site.

Evaluation of the effect of adjunctive diode laser application on peri-implant crevicular fluid biomarker levels: a randomized controlled trial

ObjectivesTo assess both the clinical and immunological effectiveness of diode laser therapy when used as an adjunct to non-surgical mechanical therapy in managing peri-implantitis.Materials and methodsA cohort of 27 participants, comprising 21 females and 6 males, agreed to take part in this investigation. 37 dental implants with peri-implantitis diagnosis were randomly allocated to either the laser group (n = 19) or the control group (n = 18). Evaluation of peri-implant clinical parameters and collection peri-implant crevicular fluid (PICF) samples occurred at baseline, as well as at 3 and 6-month follow-up intervals. The level of various biomarkers (TWEAK, IL-1β, sclerostin, IL-17, RANKL, OPG and IL-10) within the PICF were quantified using enzyme-linked immunosorbent assay.ResultsSignificant time-dependent decreases in clinical and biochemical parameters were detected in both groups compared to the baseline. There were marked differences between the groups in terms of periodontal parameters, except probing depth, and IL-1β, IL-17, sclerostin levels in PICF at 3rd month follow-up. However, no statistically significant difference was detected at 6th month.ConclusionsDiode laser seems to be a reliable tool as an adjunct for supporting the nonsurgical mechanical treatment during the early stages of peri-implantitis. Furthermore, the findings suggest that IL-17, sclerostin and IL-1β may serve as promising biomarkers for assessing efficacy of peri-implantitis treatment.Clinical relevanceBased on these outcomes, clinicians may consider the application of adjunctive use of diode laser to non-surgical peri-implantitis treatment to achieve better clinical and immunological improvements than nonsurgical peri-implantitis therapy alone in just early healing period. However, it should be noted that there was no difference between the two methods in the long term.

PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation

ObjectiveThe skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels, which were previously correlated with metabolic status of extramedullary fat depots. MethodsIn vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp1CrePparγflfl male and female mice (γOTKO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. ResultsCirculating sclerostin levels of γOTKO male and female mice were not different from control mice. Male γOTKO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with “beiging” of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOTKO males suggested profound changes in cellular metabolism, fuel transport, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, and accumulation of reactive oxygen species (ROS). ConclusionsPPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism.

Cystinosis-associated metabolic bone disease across ages and CKD stages 1-5D/T.

The pathophysiology of cystinosis-associated metabolic bone disease is complex. We hypothesized a disturbed interaction between osteoblasts and osteoclasts. Binational cross-sectional multicenter study. Hospital clinics. One hundred and three patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1-5D/T. Ten key bone markers. Skeletal complications occurred in two-thirds of the patients, with adults having a five-fold increased risk compared to children. Patients with CKD stages 1-3 showed reduced z-scores for serum phosphate and calcium, suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation. Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counterregulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia may promote progressive bone loss.

Sclerostin antibody corrects periodontal disease in type 2 diabetic mice.

Type 2 diabetes (T2D) is on the rise worldwide and is associated with various complications in the oral cavity. Using an adult-onset diabetes preclinical model, we demonstrated profound periodontal alterations in T2D mice, including inflamed gingiva, disintegrated periodontal ligaments (PDLs), marked alveolar bone loss, and unbalanced bone remodeling due to decreased formation and increased resorption. Notably, we observed elevated levels of the Wnt signaling inhibitor sclerostin in the alveolar bone of T2D mice. Motivated by these findings, we investigated whether a sclerostin-neutralizing antibody (Scl-Ab) could rescue the compromised periodontium in T2D mice. Administering Scl-Ab subcutaneously once a week for 4 weeks, starting 4 weeks after T2D induction, led to substantial increases in bone mass. This effect was attributed to the inhibition of osteoclasts and promotion of osteoblasts in both control and T2D mice, effectively reversing the bone loss caused by T2D. Furthermore, Scl-Ab stimulated PDL cell proliferation, partially restored the PDL fibers, and mitigated inflammation in the periodontium. Our study thus established a T2D-induced periodontitis mouse model characterized by inflammation and tissue degeneration. Scl-Ab emerged as a promising intervention to counteract the detrimental effects of T2D on the periodontium, exhibiting limited side effects on other craniofacial hard tissues.

Serum level of sclerostin and vitamin D in children with epilepsy

BackgroundEpileptic children can pose an additional risk of poor bone health; this study aimed to evaluate the influence of anti-seizure medications (ASMs) on vitamin D level and sclerostin as a bone turnover biomarker in children with epilepsy.Subject and methodsThis case–control comparative study was conducted on 180 children aged from 5–18 years diagnosed with epilepsy according to the definition of the International League Against Epilepsy on ASMs for more than 3 months and were classified into 90 epileptic children on ASM monotherapy and 90 epileptic children on ASM polytherapy, in addition to 90 healthy children age- and sex-matched who served as controls. After obtaining basic data, laboratory investigations were performed, including serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, vitamin D, and serum sclerostin.ResultsWhen we compared epileptic patients to the control group, there was a statistically significant low level of vitamin D, calcium, and phosphorus and a high level of sclerostin among both epileptic groups with mono or polytherapy. Sclerostin has a statistically significant negative correlation with vitamin D, alkaline phosphatase and parathyroid hormone. Additionally, it has a negative correlation with serum phosphorus, but without a significant correlation. On the other hand, sclerostin has a statistically positive correlation with age and serum calcium, but without a significant correlation. Multiple linear regression analyses were conducted to predict the contributing factors of sclerostin. Only duration of treatment and BMI were significant predictors of high levels of sclerostin. In contrast, the other factors failed to show any significant contribution.ConclusionThe present study showed that ASMs modulate the serum levels of sclerostin and vitamin D hence, might be involved in their adverse effects on bone.

Exogenous iron caused osteocyte apoptosis, increased RANKL production, and stimulated bone resorption through oxidative stress in a murine model

Iron overload is a risk factor for osteoporosis due to its oxidative toxicity. Previous studies have demonstrated that an excessive amount of iron increases osteocyte apoptosis and receptor activator of nuclear factor κ-B ligand (RANKL) production, which stimulates osteoclast differentiation in vitro. However, the effects of exogenous iron supplementation-induced iron overload on osteocytes in vivo and its role in iron overload-induced bone loss are unknown. This work aimed to develop an iron overloaded murine model of C57BL/6 mice by intraperitoneal administration of iron dextran for two months. The iron levels in various organs, bone, and serum, as well as the microstructure and strength of bone, apoptosis of osteocytes, oxidative stress in bone tissue, and bone formation and resorption, were assessed. The results showed that 2 months of exogenous iron supplementation significantly increased iron levels in the liver, spleen, kidney, bone tissue, and serum. Iron overload negatively affected bone microstructure and strength. Osteocyte apoptosis and empty lacunae rate were elevated by exogenous iron. Iron overload upregulated RANKL expression but had no significant impact on osteoprotegerin (OPG) and sclerostin levels. Static and dynamic histologic analyses and serum biochemical assay showed that iron overload increased bone resorption without significantly affecting bone formation. Exogenous iron promoted oxidative stress in osteocytes in vivo and in vitro. Additional supplementation of iron chelator (deferoxamine) or N-acetyl-l-cysteine (NAC) partially alleviated bone loss, osteocyte apoptosis, osteoclast formation, and oxidative stress due to iron overload. These findings, in line with prior in vitro studies, suggest that exogenous iron supplementation induces osteoclastogenesis and osteoporosis by promoting osteocyte apoptosis and RANKL production via oxidative stress.

Sclerostin and Wnt Signaling in Idiopathic Juvenile Osteoporosis Using High-Resolution Confocal Microscopy for Three-Dimensional Analyses.

Idiopathic juvenile osteoporosis (IJO) is a rare condition characterized by low bone mass that can increase the risk of fractures in children. Treatment options for these patients are limited as the molecular mechanisms of disease initiation and progression are incompletely understood. Sclerostin inhibits canonical Wnt signaling, which is important for the bone formation activity of osteoblasts, and elevated sclerostin has been implicated in adult osteoporosis. To evaluate the role of sclerostin in IJO, high-resolution confocal microscopy analyses were performed on bone biopsies collected from 13 pediatric patients. Bone biopsies were stained with sclerostin, and β-catenin antibodies showed elevated expression across osteocytes and increased sclerostin-positive osteocytes in 8 of the 13 total IJO patients (62%). Skeletal sclerostin was associated with static and dynamic histomorphometric parameters. Further, colocalization analyses showed that bone sclerostin colocalized with phosphorylated β-catenin, a hallmark of Wnt signaling that indicates Wnt inhibition. In contrast, sclerostin-positive osteocytes were not colocalized with an "active" unphosphorylated form of β-catenin. These results support a model that altered levels of sclerostin and Wnt signaling activity occur in IJO patients.

Anti-sclerostin antibody – A potential therapeutic target for periodontal bone regeneration

Sclerostin is a glycoprotein predominantly released by specialized bone-forming cells (osteocytes). It serves as a principal inhibitor of osteogenesis and plays a key act in modulating the metabolism of alveolar bone. Sclerostin is shown to contribute to the occurrence of periodontitis by regulating the remodeling of the alveolar bone. A monoclonal antibody which antagonizes sclerostin has become extremely useful for osteoanabolic therapies. Romosozumab is an Food and Drug Administration-approved anti-sclerostin antibody that has shown promising results in the treatment of osteoporosis. Research is being conducted on the effect of anti-sclerostin antibody (Scl-Ab) as a therapeutic option in the management of periodontitis, and up till now, the results are promising. A comprehensive review of the literature was done using the PubMed database and Google Scholar. Research articles published before April 2023 with the search terms “sclerostin,” “periodontitis,” and “anti-sclerostin antibody” (Scl-Ab) were included. Most of the studies point toward a definitive association between chronic periodontitis and the levels of sclerostin. Numerous investigations underscore the significance of evaluating sclerostin levels as a diagnostic marker for periodontitis, and the application of anti-sclerostin antibodies as a potential therapeutic option for managing periodontitis and peri-implant diseases. However, further researches are required to delve into the therapeutic effects and possible side effects of Scl-Ab. Sclerostin antibodies show promise as an anabolic drug that enhances bone mass and could potentially become a viable therapeutic alternative for addressing periodontal conditions in future.

Bone Turnover Markers and Wnt Signaling Modulators in Early Complex Regional Pain Syndrome. A Pre-specified Observational Study.

To explore serum levels of some bone turnover markers and the involvement of the Wnt signaling in CRPS-1. Query ID="Q1" Text="Please check and confirm whether the edit made to the article title is in order." We conducted an observational study on patients with early CRPS-1 recruited before any treatment. Clinical measures were assessed together with biochemical evaluation. Values of sclerostin, DKK1, CTX-I, and P1NP were compared with sex-age-matched healthy controls (HCs). We enrolled 34 patients diagnosed with CRPS-1 (mean age 59.3 ± 10.6years, Male/Female 10/24), median disease duration = 2weeks (IQR 1-5); median VAS score = 76 (IQR 68-80). Foot localization was slightly more frequent than hand localization (18/16). No statistically significant difference was found between CRPS-1 patients and HCs for CTX-I (0.3 ± 0.1ng/ml vs 0.3 ± 0.1, p = 0.140), while mean serum values of P1NP were significantly higher in CRPS-1 patients compared to HCs (70.0 ± 38.8ng/ml vs 50.1 ± 13.6, p = 0.005). Mean levels of sclerostin and DKK1 were lower in CRPS-1 patients vs HCs (sclerostin 28.4 ± 10.8pmol/l vs 34.1 ± 11.6, p = 0.004; DKK1 12.9 ± 10.8pmol/l vs 24.1 ± 11.9, p = 0.001). No statistically significant difference was found for all biochemical assessments in a subgroup of fracture-induced CRPS-1. No statistically significant differences were observed according to disease localization, disease duration, presence of hyperalgesia, allodynia, sudomotor alterations, and mild or moderate/severe swelling. No significant correlation emerged between sclerostin, DKK1 levels, baseline VAS score, or McGill Pain Questionnaire score. Bone involvement in early CRPS-1 does not seem to rely on increased osteoclast activity. Conversely, a serum marker of bone formation resulted increased. Both Sclerostin and DKK1 showed decreased values, probably suggesting a widespread osteocyte loss of function.Trial registration number: Eudract Number: 2014-001156-28.