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

BACKGROUND: Osteoporosis (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. METHODS: The 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. RESULTS: Diabetic 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. CONCLUSIONS: Sclerostin and CTRP3 levels are involved in OP in postmenopausal diabetic patients.

GDF11 (Protein of Juvenility) and GDF15 (Protein of Senility) in the Plasma of Patients with Sleep Apnea Syndrome: a Pilot Study.

We performed a matched-pair analysis of the content of GDF11 and GDF15 proteins in the plasma of patients (56 middle-aged men) with obstructive sleep apnea syndrome (OSAS) and healthy volunteers (27 men with no complaints of sleep disorders). The groups were comparable in terms of age and presence of chronic diseases. No statistically significant differences in GDF11 content in the studied groups were revealed, while the content of GDF15 in the OSAS group was 1.3 times higher. These results require further research from the viewpoint of geriatric somnology and molecular biology.

[Correlation between serum growth differentiation factor 11 level and severity of coronary artery disease in patients with acute myocardial infarction].

Objective: To investigate the correlation between serum growth differentiation factor 11 (GDF11) level and coronary artery lesions in patients with ST-segment elevation myocardial infarction (STEMI), and the predictive efficacy of nomogram risk prediction model based on GDF11 combined with traditional risk factors on the occurrence of STEMI. Methods: This study was a retrospective cross-sectional study. Patients hospitalized in the Department of Cardiology of the 904th Hospital of Joint Logistic Support Force of People's Liberation Army of China from 2016 to 2018 were selected and divided into control group and STEMI group. The demographic data, blood lipid level, laboratory indicators of blood and GDF11 level were collected. Logistic regression analysis screened out independent correlated factors for the occurrence of STEMI. Spearman correlation analysis clarified the correlation of each indicator with the SYNTAX or Gensini scores. A nomogram risk prediction model for the risk of STEMI occurrence and the receiver operating characteristic curve was used to compare the prediction efficiency of each model. Results: A total of 367 patients were enrolled, divided into control group (n=172) and STEMI group (n=195), age (66.5±11.8), male 222 (60.49%). The serum GDF11 level of STEMI group was significantly lower than that of the control group (36.20 (16.60, 70.75) µg/L vs. 85.00 (53.93, 117.10) µg/L, P<0.001). The results of multivariate logistic regression analysis showed serum GDF11(OR=0.98, 95%CI: 0.97-0.99) and traditional independent risk factors such as smoking, diabetes, C-reactive protein, homocysteine, lipoprotein (a) and apolipoprotein A1/B were independent correlate factors for the occurrence of STEMI (P<0.05). Spearman correlation analysis showed that serum GDF11 was negatively correlated with SYNTAX score and Gensini score (P<0.05). The nomogram model constructed by serum GDF11 combined with traditional independent risk factors (AUC=0.85, 95%CI: 0.81-0.89) had better predictive value for the occurrence of STEMI than the traditional nomogram model constructed by independent risk factors(AUC=0.80, 95%CI:0.75-0.84) or serum GDF11 (AUC=0.76, 95%CI: 0.72-0.81), all P<0.01. Conclusions: Serum GDF11 is an independent correlate factor in the occurrence of STEMI and is negatively correlated with the severity of coronary artery lesions in patients with STEMI. The nomogram model constructed based on GDF11 combined with traditional risk factors can be a good predictor for the occurrence of STEMI.

Decreased Serum Wnt Antagonist Levels in Patients With Active Acromegaly.

OBJECTIVE: The Wnt signaling pathway is an important modulator of bone metabolism. This study aims to clarify the changes in Wnt antagonists in active and biochemically controlled acromegalic patients. METHODS: We recruited 77 patients recently diagnosed with acromegaly. Of those, 41 patients with complete follow-up data were included. Thirty healthy patients matched for age, sex, and body mass index served as controls. At baseline and posttreatment, Wnt antagonists (sclerostin [SOST], dickkopf-related protein 1 [DKK-1], and Wnt inhibitory factor 1 [WIF-1]), bone turnover markers (osteocalcin, procollagen type 1 N-terminal propeptide [P1NP], and C-terminal telopeptide of type 1 collagen [CTX]) and the bone remodeling index were investigated. RESULTS: Acromegalic patients had higher serum osteocalcin, P1NP, and CTX and a higher bone remodeling index than controls (P < .01). Serum SOST, DKK-1, and WIF-1 levels were significantly decreased in patients compared to controls (all P < .01). Serum SOST and WIF-1 levels were negatively correlated with growth hormone levels; SOST levels were positively correlated with WIF-1. After treatment, serum bone turnover markers and the bone remodeling index decreased, while SOST and WIF-1 significantly increased (P < .05). DKK-1 levels did not change compared to baseline (P > .05). In biochemically controlled patients, SOST and WIF-1 levels and bone turnover markers were restored and did not differ from those of the control participants (all P > .05). CONCLUSION: Patients with active acromegaly exhibited significantly decreased Wnt antagonist levels. The reduction in Wnt antagonists is a compensatory mechanism to counteract increased bone fragility in active acromegaly.

The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis.

GDF11 is a secreted factor in the TGFß family of cytokines. Its nearest neighbor evolutionarily is myostatin, a factor discovered as being a negative regulator of skeletal muscle growth. High profile studies several years ago suggested that GDF11 declines with age, and that restoration of systemic GDF11 to 'youthful' levels is beneficial for several age-related conditions. Particularly surprising was a report that supplementation of GDF11 aided skeletal muscle regeneration, as its homolog, myostatin, has the opposite role. Given this apparent contradiction in functionality, multiple independent labs sought to discern differences between the two factors and better elucidate age-related changes in circulating GDF11, with most failing to reproduce the initial finding of declining GDF11 levels, and, importantly, all subsequent studies examining the effects of GDF11 on skeletal muscle described an inhibitory effect on regeneration - and that higher doses induce skeletal muscle atrophy and cachexia. There have also been several studies examining the effect of GDF11 and/or the downstream ActRII pathway on cardiac function, along with several interesting reports on bone. A review of the GDF11 literature, as it relates in particular to aging and skeletal muscle, cardiac and bone biology, is presented.

Targeted Approach to Distinguish and Determine Absolute Levels of GDF8 and GDF11 in Mouse Serum.

Growth differentiation factor 11 (GDF11) is a TGF-ß superfamily circulating factor that regulates cardiomyocyte size in rodents, sharing 90% amino acid sequence identity in the active domains with myostatin (GDF8)-the major determinant of skeletal muscle mass. Conflicting data on age-related changes in circulating levels have been reported mainly due to the lack of specific detection methods. More recently, liquid chromatography tandem mass spectrometry (LC-MS/MS) based assay showed that the circulating levels of GDF11 do not change significantly throughout human lifespan, but GDF8 levels decrease with aging in men. Here a novel detection method is demonstrated based on parallel reaction monitoring LC-MS/MS assay combined with immunoprecipitation to reliably distinguish GDF11 and GDF8 as well as determine their endogenous levels in mouse serum. The data indicate that both GDF11 and GDF8 circulating levels significantly decline with aging in female mice.

Circulating Myostatin Levels Decrease Transiently after Implantation of a Hip Hemi-Arthroplasty.

INTRODUCTION: Muscle and bone metabolism are both important for the healing of fractures and the regeneration of injured muscle tissue. The aim of this investigation was to evaluate myostatin and other regulating factors in patients with hip fractures who underwent hemi-arthroplasty. METHODS: Serum levels of myostatin (MSTN), follistatin (FSTN), dickkopf-1 (Dkk1), and periostin (PSTN) as well as markers of bone turnover were evaluated in patients with hip fractures before surgery and twice in the 2 weeks after surgery. These parameters were also evaluated in age- and gender-matched subjects without major musculoskeletal injury. RESULTS: MSTN was transiently reduced; its opponent FSTN was transiently increased. Dkk1, the negative regulator of bone mass, and PSTN, a marker of subperiosteal bone formation, increased after surgery. With regard to markers of bone turnover, resorption was elevated during the entire period of observation whereas the early bone formation marker N-terminal propeptide of type I collagen was elevated 12 days after surgery. CONCLUSIONS: Unexpectedly, MSTN, a negative regulator of muscle growth, was reduced after surgery compared with before surgery. As musculoskeletal markers are altered during bone healing, they do not reflect general bone metabolism after fracture or joint arthroplasty. This is important because many elderly patients receive treatment for osteoporosis.

Integrative Approach to Assessing the Complex of Correlations between Indicators of Physiological Functions.

We present the results of application of the combined correlation matrix method in some clinical studies. A practical algorithm is proposed for constructing a correlation matrix that compactly reflects a large number of interconnections for the situations when several diagnostic methods are used in an experimental clinical or preclinical trial. Several approaches to assessing and displaying the relationships are demonstrated for comparison.

A heterodimer formed by bone morphogenetic protein 9 (BMP9) and BMP10 provides most BMP biological activity in plasma.

Bone morphogenetic protein 9 (BMP9) and BMP10 are the two high-affinity ligands for the endothelial receptor activin receptor-like kinase 1 (ALK1) and are key regulators of vascular remodeling. They are both present in the blood, but their respective biological activities are still a matter of debate. The aim of the present work was to characterize their circulating forms to better understand how their activities are regulated in vivo First, by cotransfecting BMP9 and BMP10, we found that both can form a disulfide-bonded heterodimer in vitro and that this heterodimer is functional on endothelial cells via ALK1. Next, we developed an ELISA that could specifically recognize the BMP9-BMP10 heterodimer and which indicated its presence in both human and mouse plasma. In addition to using available Bmp9-KO mice, we generated a conditional Bmp10-KO mouse strain. The plasma from Bmp10-KO mice, similarly to that of Bmp9-KO mice, completely lacked the ability to activate ALK1-transfected 3T3 cells or phospho-Smad1-5 on endothelial cells, indicating that the circulating BMP activity is mostly due to the BMP9-BMP10 heterodimeric form. This result was confirmed in human plasma that had undergone affinity chromatography to remove BMP9 homodimer. Finally, we provide evidence that hepatic stellate cells in the liver could be the source of the BMP9-BMP10 heterodimer. Together, our findings demonstrate that BMP9 and BMP10 can heterodimerize and that this heterodimer is responsible for most of the biological BMP activity found in plasma.

A distinct bone phenotype in ADPKD patients with end-stage renal disease.

Autosomal dominant polycystic kidney disease (ADPKD) is among the most common hereditary nephropathies. Low bone turnover osteopenia has been reported in mice with conditional deletion of the PKD1 and PKD2 genes in osteoblasts, and preliminary clinical data also suggest suppressed bone turnover in patients with ADPKD. The present study compared the bone phenotype between patients with end stage renal disease (ESRD) due to ADPKD and controls with ESRD due to other causes. Laboratory parameters of bone mineral metabolism (fibroblast growth factor 23 and sclerostin), bone turnover markers (bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b) and bone mineral density (BMD, by dual energy x-ray absorptiometry, DXA) were assessed in 518 patients with ESRD, including 99 with ADPKD. Bone histomorphometry data were available in 71 patients, including 10 with ADPKD. Circulating levels of bone alkaline phosphatase were significantly lower in patients with ADPKD (17.4 vs 22.6 ng/mL), as were histomorphometric parameters of bone formation. Associations between ADPKD and parameters of bone formation persisted after adjustment for classical determinants including parathyroid hormone, age, and sex. BMD was higher in skeletal sites rich in cortical bone in patients with ADPKD compared to non-ADPKD patients (Z-score midshaft radius -0.04 vs -0.14; femoral neck -0.72 vs -1.02). Circulating sclerostin levels were significantly higher in ADPKD patients (2.20 vs 1.84 ng/L). In conclusion, patients with ESRD due to ADPKD present a distinct bone and mineral phenotype, characterized by suppressed bone turnover, better preserved cortical BMD, and high sclerostin levels.

Relationship between serum level of growth differentiation factors 8, 11 and bone mineral density in girls with anorexia nervosa.

BACKGROUND: Adolescents with anorexia nervosa (AN) have low body mass and low bone mineral density (BMD). Growth differentiation factor 8 (Myostatin, GDF8) and its homologue growth differentiation factor 11 (GDF11), members of the TGF-ß super-family, play an important role in muscle regeneration and bone metabolism in healthy individuals. However, their association with BMD in AN is unknown. The present study was undertaken to investigate the relationship between GDF8, GDF11 and BMD in adolescent girls with AN. METHODS: Serum GDF8, GDF11 and BMD were determined in 25 girls (12-16 years old) with AN and 31 healthy girls (12-16 years old). RESULTS: Growth differentiation factor 8 levels were lower in AN subjects. On the contrary, GDF11 levels were higher in AN subjects than controls. There was no relationship between GDF8 and BMD. A significant negative correlation between GDF11 and BMD was found. In multiple linear stepwise regression analysis, BMI, 25-hydroxyvitamin D, GDF11, or lean mass, but not fat mass and GDF8, were independent predictors of BMD in the AN and control groups separately. CONCLUSIONS: Growth differentiation factor 11 was independent predictor of BMD in girls with AN. It suggested that GDF11 exerts a negative effect on bone mass.

Serum Sclerostin and Bone Morphogenetic Protein-2 Levels in Patients with Ankylosing Spondylitis: A Meta-Analysis.

Various studies have investigated the serum sclerostin and bone morphogenetic protein-2 (BMP-2) levels in patients with ankylosing spondylitis (AS), but the results were inconsistent. The aim of this meta-analysis was to synthetically assess the associations of serum levels of sclerostin and BMP-2 with AS. Multiple electronic databases were searched to locate relevant articles published before November 2018. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Totally, 21 studies were included. Meta-analysis results showed no significant difference between AS group and control group in serum sclerostin levels (SMD = 0.098, 95% CI - 0.395 to 0.591, p = 0.697). Nevertheless, serum BMP-2 levels in AS patients were higher than that in controls (SMD = 1.184, 95% CI 0.209 to 2.159, p = 0.017). Subgroup analysis demonstrated that European and South American AS patients had lower serum levels of sclerostin than controls. AS patients with age ≥ 40 years, erythrocyte sedimentation rate (ESR) ≤ 20 mm/h and Bath Ankylosing Spondylitis Functional Index (BASFI) < 4 had statistically significant lower serum sclerostin concentrations compared to controls. Chinese and Korean AS patients as well as patients with lower CRP had higher serum BMP-2 levels than controls, and country may be a source of heterogeneity across the studies. No publication bias existed and sensitivity analysis confirmed the stability of results. Serum BMP-2, but not sclerostin levels may be closely related to the development of AS.

GDF11 impairs liver regeneration in mice after partial hepatectomy.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-ß superfamily. The rejuvenative effect of GDF11 has been called into question recently, and its role in liver regeneration is unclear. Here, we investigated the pathophysiologic role of GDF11, as well as its plausible signaling mechanisms in a mouse model of partial hepatectomy (PH). We demonstrated that both serum and hepatic GDF11 protein expression increased following PH. Treatment with adeno-associated viruses-GDF11 and recombinant GDF11 protein severely impaired liver regeneration, whereas inhibition of GDF11 activity with neutralizing antibodies significantly improved liver regeneration after PH. In vitro, GDF11 treatment significantly delayed cell proliferation and induced cell-cycle arrest in α mouse liver 12 (AML12) cells. Moreover, GDF11 activated TGF-ß-SMAD2/3 signaling pathway. Inhibition of GDF11-induced SMAD2/3 activity significantly blocked GDF11-mediated reduction in cell proliferation both in vivo and in vitro. In the clinical setting, GDF11 levels were significantly elevated in patients after hepatectomy. Collectively, these results indicate that rather than a 'rejuvenating' agent, GDF11 impairs liver regeneration after PH. Suppression of cell-cycle progression via TGF-ß-SMAD2/3 signaling pathway may be a key mechanism by which GDF11 inhibits liver regeneration.

Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers
.

INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.

Association of serum bone- and muscle-derived factors with age, sex, body composition, and physical function in community-dwelling middle-aged and elderly adults: a cross-sectional study.

BACKGROUND: Understanding interactions between bone and muscle based on endocrine factors may help elucidate the relationship between osteoporosis and sarcopenia. However, whether the abundance or activity of these endocrine factors is affected by age and sex or whether these factors play a causal role in bone and muscle formation and function is unclear. We aimed to evaluate the association of serum bone- and muscle-derived factors with age, sex, body composition, and physical function in community-dwelling middle-aged and elderly adults. METHODS: In all, 254 residents (97 men, 157 women) participated in this cross-sectional study conducted in Japan. The calcaneal speed of sound (SOS) was evaluated by quantitative ultrasound examination. Skeletal muscle mass index (SMI) was calculated by bioelectrical impedance analysis. Grip strength was measured using a dynamometer. Gait speed was measured by optical-sensitive gait analysis. Serum sclerostin, osteocalcin (OC), insulin-like growth factor-1 (IGF-1), myostatin, and tartrate-resistant acid phosphatase-5b (TRACP-5b) concentrations were measured simultaneously. The difference by sex was determined using t test. Correlations between serum bone- and muscle-derived factors and age, BMI, SOS, SMI, grip strength, gait speed, and TRACP-5b in men and women were determined based on Pearson's correlation coefficients. Multiple regression analysis was performed using the stepwise method. RESULTS: There was no significant difference with regard to age between men (75.0 ± 8.9 years) and women (73.6 ± 8.1 years). Sclerostin was significantly higher in men than in women and tended to increase with age in men; it was significantly associated with SOS and TRACP-5b levels. OC was significantly higher in women than in men and was significantly associated with TRACP-5b levels and age. IGF-1 tended to decrease with age in both sexes and was significantly associated with SOS and body mass index. Myostatin did not correlate with any assessed variables. CONCLUSIONS: Sclerostin was significantly associated with sex, age, and bone metabolism, although there was no discernable relationship between serum sclerostin levels and muscle function. There was no obvious relationship between OC and muscle parameters. This study suggests that IGF-1 is an important modulator of muscle mass and function and bone metabolism in community-dwelling middle-aged and elderly adults.

Once-weekly teriparatide reduces serum sclerostin levels in postmenopausal women with osteoprosis.

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. METHODS: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. RESULTS: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. CONCLUSIONS: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.

Exercise Alleviates Osteoporosis in Rats with Mild Chronic Kidney Disease by Decreasing Sclerostin Production.

Chronic kidney disease-mineral bone disorder (CKD-MBD), comprising mineral, hormonal, and bone metabolic imbalance, is a major CKD-related issue; it causes osteoporosis prevalence in CKD patients. Osteocyte-derived sclerostin inhibits the osteogenic Wnt/ß-catenin signaling pathway; its levels rise when kidney function declines. Exercise modulates the physiological functions of osteocytes, potentially altering sclerostin production. It may aid bone and mineral electrolyte homeostasis in CKD. Mild CKD was induced in rats by partial nephrectomy. They were divided into: sham (no CKD), CKD, and CKD + exercise (8 weeks of treadmill running) groups. Micro-CT scanning demonstrated that the CKD + exercise-group rats had a higher bone mineral density (BMD) of the spine and femoral metaphysis and higher femoral trabecular bone volume than the CKD-group rats. Bone formation rates were not significantly different. The CKD + exercise-group rats had lower serum sclerostin (157.1 ± 21.1 vs 309 ± 38.1 pg/mL, p < 0.05) and CTX-1 (bone resorption marker) levels. Immunohistochemistry revealed higher tibial ß-catenin concentrations in the CKD + exercise-group rats. Serum FGF-23, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), calcium, and phosphate levels showed no significant differences between these groups. Thus, exercise improves BMD and bone microstructure in mild CKD by inhibiting sclerostin production, but does not alter serum minerals.

[Wnt signaling and bone metabolic diseases.]

Wnt signaling is known to be involved in metabolic bone disorders. Serum levels of sclerostin, a bone-specific protein that inhibits Wnt signaling, have been investigated in a variety of metabolic bone disorders. Serum sclerostin levels are positively correlated with bone mineral density in patients with osteoporosis. Elderly women with high serum sclerostin levels, however, are at increased risk of bone fractures. Since serum sclerostin levels are low in primary hyperparathyroidism and high in hypoparathyroidism, parathyroid hormone could be classified as a factor that regulates sclerostin levels. Serum sclerostin levels are high in glucocorticoid-induced osteoporosis and diabetes mellitus, which feature reduced bone formation. Finally, serum sclerostin levels increase with decreasing renal function. These findings highlight the potential of serum sclerostin levels as a new index for bone assessments which are different in nature from bone mineral density and bone metabolic markers.

High levels of serum sclerostin and DKK1 in a case of Klippel-Trénaunay syndrome.

Klippel-Trénaunay syndrome (KTS) is described as a complex syndrome characterized by various combinations of capillary, venous, and lymphatic malformations associated with bone and soft tissue hypertrophy. We report a case of a 67-year-old postmenopausal Caucasian women with KTS that shows elevated levels of sclerostin and Dickkopf-related protein 1 (DKK1). Dual-energy X-ray absorptiometry (DXA) BMD T-scores at lumbar spine and femur were normal. Serum calcium and phosphorus levels were consistently normal, 25-hydroxyvitamin D (25OHD) < 30 ng/mL, and normal parathyroid hormone (PTH). Turnover markers (serum osteocalcin [OCN], and carboxy-terminal cross-linking telopeptide of type 1 collagen [CTx]) were in the reference limits. It is interesting to note that the serum levels of sclerostin and DKK-1 were significantly higher in our patient with KTS than in a healthy volunteer (control), without impact on bone mineral density and bone formation markers. In fact, in our patient, the BMD at lumbar spine and femur was normal, and osteocalcin was not suppressed. Based on what is known, we would have expected to find low levels of the inhibitors of the Wnt system, perhaps we can explain the data as a response to the compensation for ß-catenin hyper-transformation.

Genetic variation in Wnt/ß-catenin and ER signalling pathways in female and male elite dancers and its associations with low bone mineral density: a cross-section and longitudinal study.

The association of genetic polymorphisms with low bone mineral density in elite athletes have not been considered previously. The present study found that bone mass phenotypes in elite and pre-elite dancers are related to genetic variants at the Wnt/ß-catenin and ER pathways. INTRODUCTION: Some athletes (e.g. gymnasts, dancers, swimmers) are at increased risk for low bone mineral density (BMD) which, if untreated, can lead to osteoporosis. To investigate the association of genetic polymorphisms in the oestrogen receptor (ER) and the Wnt/ß-catenin signalling pathways with low BMD in elite and pre-elite dancers (impact sport athletes). METHODS: The study included three phases: (1) 151 elite and pre-elite dancers were screened for the presence of low BMD and traditional osteoporosis risk factors (low body weight, menstrual disturbances, low energy availability); (2) a genetic association study was conducted in 151 elite and pre-elite dancers and age- and sex- controls; (3) serum sclerostin was measured in 101 pre-elite dancers and age- and sex-matched controls within a 3-year period. RESULTS: Eighty dancers revealed low BMD: 56.3% had at least one traditional osteoporosis risk factor, whereas 28.6% did not display any risk factor (37.2% revealed traditional osteoporosis risk factors, but had normal BMD). Body weight, menstrual disturbances and energy availability did not fully predict bone mass acquisition. Instead, genetic polymorphisms in the ER and Wnt/ß-catenin pathways were found to be risk factors for low BMD in elite dancers. Sclerostin was significantly increased in dancers compared to controls during the 3-year follow-up (p < 0.05). CONCLUSIONS: Elite and pre-elite dancers demonstrate high prevalence of low BMD, which is likely related to genetic variants at the Wnt/ß-catenin and ER pathways and not to factors usually associated with BMD in athletes (body weight, menstrual disturbances, energy deficiency).