Role Of Sclerostin Research Articles

Evaluation of Renal Osteodystrophy and Serum Bone-Related Biomarkers in a Peritoneal Dialysis Population.

The spectrum of renal osteodystrophy (ROD) in peritoneal dialysis (PD) patients remains to be clarified. Ideal intact parathormone (iPTH) levels range is still not defined. The role of sclerostin, dickkopf-related protein 1, osteoprotegerin, and receptor activator for nuclear factor κB ligand for the diagnosis of ROD needs to be elucidated. In this cross-sectional study, tetracycline double-labeled bone biopsy was performed in 49 patients with histomorphometric analysis according Kidney Disease Improving Global Outcomes (KDIGO) guidelines. All patients were treated with biocompatible PD solutions, with calcium concentration of 1.25 mmol/L. Adynamic bone was the most frequent diagnosed pattern (42.9%) followed by hyperparathyroid-related bone disease (28.6%). Twenty-two percent of patients had normal bone. In patients with iPTH within the KDIGO recommended range for dialysis patients, adynamic bone was found in 59% of cases. Median (range) iPTH in patients with adynamic bone was 312 (60-631) pg/mL. Median (range) levels of sclerostin varied from 1511.64 (458.84-6387.70)pg/mL in patients with hyperparathyroid bone disease to 2433.1 (1049.59-11354.52)pg/mL in patients with adynamic bone. Sclerostin/iPTH ratio was the best marker of low turnover disease but iPTH performed best in the diagnosis of high turnover disease. Calcium mass transfer was positive in patients with low bone volume. Adynamic bone is the most frequent ROD pattern in contemporary PD. Our results suggest the need to review the iPTH target range for this population. The sclerostin/iPTH ratio showed improved performance compared to iPTH for the diagnosis of low turnover bone. © 2022 American Society for Bone and Mineral Research (ASBMR).

P1244MILD DIFFERENCES IN CARDIAC CALCIFICATION BETWEEN WILD TYPE AND SCLEROSTIN KNOCKOUT MICE WITH CKD

Abstract Background and Aims Ectopic soft tissue calcifications, especially cardiovascular calcifications, are frequently observed in patients with chronic kidney disease (CKD) and are associated with increased morbidity and mortality. Sclerostin, a well-known inhibitor of bone formation, shows significantly increased serum levels in CKD patients. Since the process of ectopic calcification shares many similarities with physiological bone formation, we investigated a possible role for sclerostin in ectopic calcification development. Method CKD was induced in wild type (WT) (n=21) and sclerostin knockout (Sost ko) mice (n = 21), both on a C57Bl6/J background, by the alternate administration of a 0.30% and 0.15% adenine supplemented diet, containing 1% phosphate. A normal renal function control group receiving standard mouse chow (WT C57Bl6/J n = 8) was also included in the study. Serum creatinine and phosphate levels were measured at the start and end of the study to assess CKD development. At sacrifice, the calcium content of the kidneys, heart and aorta was determined by flame atomic absorption spectrometry. Results The adenine-supplemented diet led to a clear induction of CKD in both the Sost ko and wild type mice, as reflected by increased serum creatinine (0.38 ± 0.09 mg/dL in control mice vs 0.65 ± 0.18 mg/dL in adenine-exposed mice, p<0.0001) and phosphate levels (9.12 ± 1.16 mg/dL in control mice vs 19.03 ± 3.11 mg/dL in adenine-exposed mice, p<0.0001). The Sost ko and WT mice receiving the adenine diet, developed the same degree of renal failure, since there were no differences in serum levels of creatinine (p=0.0507) and phosphate (p=0.4890). Significantly higher amounts of calcium were measured in the kidney (0.05 ± 0.01 mg/g wet tissue vs 3.70 ± 2.00 mg/g wet tissue, p<0.0001) and the heart (0.03 ± 0.01 mg/g wet tissue vs 0.07 ± 0.04 mg/g wet tissue, p<0.0001) of adenine-exposed mice, compared to mice receiving the control diet. Furthermore, Sost ko mice had a significantly higher calcium content in the heart compared to the WT mice with renal failure (0.05 ± 0.03 mg/g wet tissue in WT mice vs 0.08 ± 0.05 mg/g wet tissue in Sost ko mice, p = 0.0029). No differences were observed in aortic calcium content between control mice and mice with renal failure. Conclusion In this study we managed to develop a mouse model of CKD-induced soft tissue calcification in the heart and kidneys of the animals, however no calcifications developed in the aorta. The higher calcium content that was observed in the heart of Sost ko mice compared to WT mice, might be an indication of a protective function of sclerostin during ectopic cardiac calcification

The Role of Sclerostin in Bone and Ectopic Calcification.

Sclerostin, a 22-kDa glycoprotein that is mainly secreted by the osteocytes, is a soluble inhibitor of canonical Wnt signaling. Therefore, when present at increased concentrations, it leads to an increased bone resorption and decreased bone formation. Serum sclerostin levels are known to be increased in the elderly and in patients with chronic kidney disease. In these patient populations, there is a high incidence of ectopic cardiovascular calcification. These calcifications are strongly associated with cardiovascular morbidity and mortality. Although data are still controversial, it is likely that there is a link between ectopic calcification and serum sclerostin levels. The main question, however, remains whether sclerostin exerts either a protective or deleterious role in the ectopic calcification process.

The Effects of Sclerostin on the Immune System.

We reviewed recent progress on the role of sclerostin (SOST) and its effects on the immune system in order to summarize the current state of knowledge in osteoimmunology, in regard to hematopoiesis, lymphopoiesis, and inflammation. Changes in sclerostin levels affect distinct niches within the bone marrow that support hematopoietic stem cells and B cell development. Sclerostin's regulation of adipogenesis could also be important for immune cell maintenance with age. Surprisingly, B cell development in the bone marrow is influenced by Sost produced by mesenchymal stem cells and osteoblasts, but not by osteocytes. Additionally, extramedullary hematopoiesis in the spleen and increased pro-inflammatory cytokine levels in the bone marrow are observed in global Sost-/- mice. In addition to changes in bone marrow density, sclerostin depletion affects B lymphopoiesis and myelopoiesis, as well as other changes within the bone marrow cavity that could affect hematopoiesis. It is therefore important to monitor for hematopoietic changes in patients receiving sclerostin-depleting therapies.

The role of sclerostin in knee osteoarthritis and its relation to disease progression

BackgroundOsteoarthritis (OA) is a common joint disease especially in aging population and is characterized by progressive degeneration of articular cartilage, osteophyte formation, and subsequent joint space narrowing. Sclerostin, a protein product of the SOST gene, secreted mainly by osteocytes causes inhibition of Wnt/ β-catenin signaling pathway and bone morphogenetic protein, therefore may affect bone formation and bone remodeling in OA.AimThe aim was to assess serum sclerostin level in patients with knee osteoarthritis (KOA) and its relation to disease severity.Patients and methodsA total of 80 participants (50 KOA patients and 30 healthy controls) were recruited in the present study. Sclerostin level in plasma was assessed using an enzyme-linked immunosorbent assay. OA grading was performed using the Kellgren–Lawrence classification. Assessment of physical disability was done by Western Ontario and McMaster universities Arthritis index score and health assessment questionnaire score.ResultsPlasma sclerostin levels were significantly lower in patients with OA than in healthy controls (P<0.001). Moreover, serum sclerostin level demonstrated a significant inverse correlation with the physical disability score (r=−0.506, P<0.01), age (r=−0.295, P<0.01), disease duration (P<0.05), and radiographic severity of KOA (P<0.001). By univariate regression analysis, sclerostin was one of the strong negative predictors for severity of OA.ConclusionSclerostin was significantly lower in OA plasma samples when compared with healthy controls. Serum sclerostin level was inversely associated with the physical disability and radiographic severity of KOA. Therefore, sclerostin may be used as a biochemical marker for reflecting disease severity in primary KOA.

Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone-Vascular Axis.

Sclerostin is a well-known inhibitor of bone formation that acts on Wnt/β-catenin signaling. This manuscript considers the possible role of sclerostin in vascular calcification, a process that shares many similarities with physiological bone formation. Rats were exposed to a warfarin-containing diet to induce vascular calcification. Vascular smooth muscle cell transdifferentiation, vascular calcification grade, and bone histomorphometry were examined. The presence and/or production of sclerostin was investigated in serum, aorta, and bone. Calcified human aortas were investigated to substantiate clinical relevance. Warfarin-exposed rats developed vascular calcifications in a time-dependent manner which went along with a progressive increase in serum sclerostin levels. Both osteogenic and adipogenic pathways were upregulated in calcifying vascular smooth muscle cells, as well as sclerostin mRNA and protein levels. Evidence for the local vascular action of sclerostin was found both in human and rat calcified aortas. Warfarin exposure led to a mildly decreased bone and mineralized areas. Osseous sclerostin production and bone turnover did not change significantly. This study showed local production of sclerostin in calcified vessels, which may indicate a negative feedback mechanism to prevent further calcification. Furthermore, increased levels of serum sclerostin, probably originating from excessive local production in calcified vessels, may contribute to the linkage between vascular pathology and impaired bone mineralization.

The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines.

Wnt signaling is of high relevance in the development, homeostasis, and regeneration of oral tissues. Therefore, Wnt signaling is considered to be a potential target for therapeutic strategies. The action of Wnt is tightly controlled by the inhibitors sclerostin (SOST) and Dickkopf (DKK)-1. Given the impact of SOST and DKK-1 in hard tissue formation, related diseases and healing, it is of high relevance to understand their role in oral tissues. The clinical relevance of this knowledge is further underlined by systemic and local approaches which are currently in development for treating a variety of diseases such as osteoporosis and inflammatory hard tissue resorption. In this narrative review, we summarize the current knowledge and understanding on the Wnt signaling inhibitors SOST and DKK-1, and their role in physiology, pathology, and regeneration in oral tissues. We present this role from the perspective of the different specialties in dentistry, including endodontics, orthodontics, periodontics, and oral surgery.

Role of sclerostin, fibroblast growth factor-23, and Klotho in hemodialysis patients

Introduction Chronic kidney disease–mineral bone disorder leads to decreasing bone health. Sclerostin is produced by osteocytes similar to fibroblast growth factor-23 (FGF-23) and might upregulate the FGF-23 production by the osteocyte. FGF-23 may act as a mineralization inhibitor. Klotho serves as an obligate coreceptor for the FGF-23 and represents a marker of chronic kidney disease–mineral bone disorder. Aim We examined the association between serum sclerostin, FGF-23, Klotho, parathyroid hormone, high-sensitivity C-reactive protein (hsCRP), and phosphorus levels in hemodialysis (HD) patients. Patients and methods A total of 63 HD patients in the National Institute of Urology and Nephrology and 20 controls were enrolled in the study. Serum sclerostin, FGF-23, Klotho, parathyroid hormone, hsCRP, and phosphorus levels were assayed. Results We found that serum sclerostin, FGF-23, Klotho, and hsCRP levels of the HD patients were higher than controls [median and interquartile range are 1.379 (0.217–11.680) ng/ml, 61.71 (9.821–565.5) pg/ml, 201.74 (90.53–402.73) pg/ml, and 25.79 (12.10–41.92) mg/l vs. 0.535 (0.169–0.830) ng/ml, 33.077 (10.45–67.342) pg/ml, 349.49 (201.23–721.5) pg/ml, and 4.375 (2.27–6.21), respectively; P Conclusion There is an association between serum levels of sclerostin, phosphorus, and FGF-23 in HD patients, and Klotho may represent an early marker of renal damage.

Sclerostin and its significance for children and adolescents with type 1 diabetes mellitus (T1D).

Recent studies have shown that sclerostin, which is a negative regulator of bone formation, could play an important role in the crosstalk between bone and glucose metabolism. The role of sclerostin and its link with glucose homeostasis in type 1 diabetes mellitus (T1D) has not been yet studied extensively in children. The aim of this study was to assess sclerostin and its relationship between other bone and fat related factors as well as glucose metabolism in children and adolescents with T1D in comparison to their healthy peers. Forty patients with T1D, 18 girls, mean age 12.3 ± 4.7 yrs, and 28 healthy as controls (13.1 ± 4.2 yrs), sex and Tanner stage-matched were included into the study. Fasting blood samples for measurement of sclerostin, osteocalcin (OC), leptin, adiponectin, vitamin D, fasting glucose, lipid profile, HbA1c, and C-peptide were taken at 8.00 AM. Sclerostin levels were significantly higher in patients with T1D than in the control group (p = 0.04) without significant differences between genders. Pearson correlation coefficients revealed a positive association between serum sclerostin levels and leptin OC (r = 0.59, p < 0.001) and a negative correlation between serum sclerostin levels and leptin (r = -0.32, p = 0.02) in all of the subjects and no significant correlations between sclerostin and adiponectin, 25(OH)D3, nor lipids. In the group of T1D patients a strong positive association between serum sclerostin levels and OC (r = 0.62, p < 0.001), and a negative association between serum sclerostin levels and HbA1c and leptin levels (r = -0.33, p = 0.04; r = -0.33, p = 0.03, respectively) were found. These associations were significant also after adjusting the analysis to the age, SDS-BMI and Tanner staging. In the healthy group after adjustment to age, SDS-BMI and Tanner stage, a negative correlation between sclerostin and C-peptide (r = -0.79, p = 0.02) was found. Our data suggest a possible relationship between sclerostin and glucose metabolism in children and adolescents with T1D. It would be worth to investigate if an increase in sclerostin levels could present as a potential cause of the reduction of bone formation in T1D. Both bone-derived OC as well as fat-derived leptin seems to possibly modulate the participation of sclerostin in metabolic regulation in T1D.

Sclerostin is upregulated in the early stage of chondrogenic differentiation, but not required in endochondral ossification in vitro

Sclerostin is a potent inhibitor of the canonical Wnt signaling pathway. Wnt signaling pathways have multiple roles in the regulation of cartilage development, growth, and maintenance. This study focused on the role of sclerostin in the process of chondrogenic differentiation. We hypothesized that sclerostin is essential to induce chondrogenic differentiation and regulate endochondral ossification. ATDC5 cells were used to investigate chondrogenic differentiation and terminal calcification. During chondrogenic differentiation, intrinsic sclerostin was upregulated in the early stage, but downregulated in the late stage. Addition of sclerostin elevated expressions of Sox9 and Col2a1 (P<0.05) and reduced expressions of Runx2, Col10a1, MMP-3, MMP-13, and ADAMTS5 (P<0.05) through inhibition of the Wnt-β-catenin signaling pathway (P<0.05). Terminal calcification was significantly inhibited by sclerostin (P<0.05). In contrast, deletion of sclerostin decreased expressions of Sox9 and Col2a1 (P<0.05), increased expressions of Runx2, Col10a1, MMP-3, and MMP-13 (P<0.05), and promoted terminal calcification (P<0.05). This study provides insights into the possible role of sclerostin in the regulation of chondrogenic differentiation. Sclerostin is upregulated in the early stage of chondrogenic differentiation, but is not required in endochondral ossification. Sclerostin is a candidate modulator for chondrogenic differentiation.

Sclerostin and chronic kidney disease

Chronic kidney disease (CKD) leads to the development of mineral and skeletal disturbances. They increase the risk of fractures, cardiovascular complications and, in consequence, decrease patients’ lifespan. Wnt/β-catenin pathway plays an important role in the development and homeostasis of the skeleton. The system is tightly regulated by group of inhibitors, such as sclerostin. Sclerostin inhibits bone formation and increases its resorption. There is mounting evidence that sclerostin may take part in the progress of bone and cardiovascular complications among patients with CKD. This review presents the current state of knowledge on the role of sclerostin in bone and cardiovascular disturbances in CKD patients.

Serum sclerostin in vascular calcification and clinical outcome in chronic kidney disease.

Sclerostin, a potent soluble inhibitor of the Wnt signalling pathway, is known to inhibit bone formation by suppressing osteocytes differentiation and function. Patients with chronic kidney disease have high levels of serum sclerostin. Sclerostin has been implicated in the pathogenesis of vascular calcification, which may promote the cardiovascular events of morbidity and mortality in chronic kidney disease patients. However, the role of sclerostin in vascular calcification and clinical prognosis in chronic kidney disease remains elusive. While some studies suggested a positive correlation between serum sclerostin and vascular calcification or clinical outcome, other studies showed no or even negative correlation between them. Small sample size, heterogeneity in enrolled patients, discrepancy in anatomical structure examined and differences in the applied assays may be responsible for the discrepant results. Nonetheless, anti-sclerostin antibodies may be a new therapeutic approach to increase bone mass and strength in chronic kidney disease. This review aims to have a better understanding of the relationship of serum sclerostin with vascular calcification and clinical outcome in chronic kidney disease patients, and propose the application of anti-sclerostin therapy in chronic kidney disease.

Sclerostin deficiency modifies the development of CKD-MBD in mice.

We performed 5/6 nephrectomies in 36-week-old sclerostin-deficient (SOST-/-) B6-mice and in C57BL/6J wildtype (WT) mice. Animals received a high phosphate diet for 11weeks. The bones were analyzed by high-resolution micro-computed tomography (μCT) and quantitative bone histomorphometry. Aortic tissue was analyzed regarding the extent of vascular calcification. All nephrectomized mice had severe renal failure, and parathyroid hormone was highly increased compared to corresponding sham animals. All SOST-/- animals revealed the expected high bone mass phenotype. Overall, the bone compartment in WT and SOST-/- mice responded similarly to nephrectomy. In uremic WT animals, μCT data at both the distal femur and lumbar spine revealed significantly increased trabecular volume compared to non-uremic WTs. In SOST-/- mice, the differences between trabecular bone volume were less pronounced when comparing uremic with sham animals. Cortical thickness and cortical bone density at the distal femur decreased significantly and comparably in both genotypes after 5/6 nephrectomy compared to sham animals (cortical bone density -18% and cortical thickness -32%). Overall, 5/6 nephrectomy and concomitant hyperparathyroidism led to a genotype-independent loss of cortical bone volume and density. Overt vascular calcification was not detectable in either of the genotypes. Renal osteodystrophy changes were more pronounced in WT mice than in SOST-/- mice. The high bone mass phenotype of sclerostin deficiency was detectable also in the setting of chronic renal failure with severe secondary hyperparathyroidism.

Role of sclerostin and dkk1 in bone remodeling in type 2 diabetic patients

ABSTRACT Purpose: This study aimed to investigate the role of sclerostin and dkk1 in the bone metabolism of type 2 diabetic patients. Methods: This cross-sectional study included 95 inpatients with type 2 diabetes mellitus. We divided the patients into three groups (i.e., the normal bone mineral density (BMD) group, osteopenia group and osteoporosis group) based on their different BMD levels and measured the serum levels of sclerostin, dkk1, 25-hydroxyvitamin D3 (25OHD3), bone turnover markers and other biochemical data in each group. Results: Significantly increased levels of serum sclerostin and dkk1 were found in the osteoporosis group, even when the male and female cohorts were considered separately. Ordinal logistic regression analysis suggested that the levels of serum sclerostin were independently associated with the presence of osteopenia and osteoporosis after adjusting for age, gender and 25OHD3 (sclerostin: OR = 1.02, p = 0.001). The areal BMDs were negatively correlated with the levels of serum sclerostin and dkk1 and positively correlated with 25OHD3. In addition, age, glycosylated hemoglobin and serum sclerostin levels were predictors for N-terminal propeptide of type 1 procollagen and serum dkk1 levels were the only predictors for crosslinked carboxyterminal telopeptide in type 1 collagen. Conclusions: The sclerostin and dkk1 levels increased in conjunction with the reduction of BMD, confirming that the Wnts, inhibited by sclerostin and dkk1, were potentially responsible for bone fragility in type 2 diabetes patients with osteoporosis. Note that the serum sclerostin levels were predictors for bone formation, while the DKK1 levels predicted bone resorption.

Sclerostin and Adipose Tissue

Purpose of Review Since its discovery 15 years ago, inhibition of sclerostin has come to be identified as a potent anabolic agent. The sclerostin neutralizing antibody, romosozumab, is a promising treatment for postmenopausal osteoporosis. Animal studies also show a role of sclerostin in regulating hematopoietic cells and, more recently, adipocytes. This review will summarize the newly discovered effects of sclerostin on white, beige, and bone marrow adipocytes.

Advances in research of the role of sclerostin in bone regeneration

Advances in research of the role of sclerostin in bone regeneration

Sclerostin Promotes Bone Remodeling in the Process of Tooth Movement.

Tooth movement is a biological process of bone remodeling induced by mechanical force. Sclerostin secreted by osteocytes is mechanosensory and important in bone remodeling. However, little is known regarding the role of sclerostin in tooth movement. In this study, models of experimental tooth movement were established in rats and mice. Sclerostin expression was investigated with immunohistochemistry staining, and osteoclastic activity was analyzed with tartrate-resistant acid phosphatase (TRAP) staining. MLO-Y4 osteocyte-like cells underwent uniaxial compression and tension stress or were cultured in hypoxia conditions. Expression of sclerostin was assessed by RT-qPCR and ELISA. MLO-Y4 cells were cultured with recombinant human sclerostin (rhSCL) interference and then co-cultured with RAW264.7 osteoclast precursor cells. Expressions of RANKL and OPG were analyzed by RT-qPCR, and osteoclastic activity was assessed by TRAP staining. During tooth movement, sclerostin was expressed differently in compression and tension sites. In SOST knock-out mice, there were significantly fewer TRAP-positive cells than in WT mice during tooth movement in compression sites. In-vitro studies showed that the expression of sclerostin in MLO-Y4 osteocyte-like cells was not different under a uniaxial compression and tension force, whereas hypoxia conditions significantly increased sclerostin expression in MLO-Y4 cells. rhSCL interference increased the expression of RANKL and the RANKL/OPG ratio in MLO-Y4 cells and the osteoclastic induction ability of MLO-Y4 cells in experimental osteocyte-osteoclast co-culture. These data suggest that sclerostin plays an important role in the bone remodeling of tooth movement.

Sclerostin's role in bone's adaptive response to mechanical loading

Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis.

Changes of serum sclerostin and Dickkopf-1 levels during the menstrual cycle. A pilot study.

Studies in postmenopausal women have identified sclerostin as a strong candidate for mediating estrogen effects on the skeleton. The effects of estradiol on sclerostin and Dickkopf-1 in younger women remain unclear. The main purpose of this study is to investigate the impact of estradiol and gonadotrophins fluctuations during the menstrual cycle on circulating sclerostin and Dickkopf-1 levels and the possible relationship of sclerostin and Dickkopf-1 with changes in N-terminal propeptide of type 1 collagen and C-telopeptide of collagen cross-links. Fourteen healthy premenopausal Caucasian women, with regular menses, aged 33.6 ± 4.5 years participated. After the first day of menstruation and every-other-day up to the next menses, fasting serum estradiol, luteinizing hormone, follicle-stimulating hormone, sclerostin, Dickkopf-1, N-terminal propeptide of type 1 collagen, and C-telopeptide of collagen cross-links levels were measured in peripheral blood. Participants completed dietary questionnaires and the International physical activity questionnaire during the cycle. Neither sclerostin nor Dickkopf-1 levels changed significantly across the menstrual cycle (p = 0.18 and p = 0.39, respectively), while N-terminal propeptide of type 1 collagen and C-telopeptide of collagen cross-links levels presented cyclic variation (p < 0.001 and p = 0.004, respectively). Baseline sclerostin (29.23 ± 10.62 pmol/L) positively correlated with N-terminal propeptide of type 1 collagen (r = 0.71, p < 0.01) and C-telopeptide of collagen cross-links (r = 0.63, p < 0.05), while Dickkopf-1 (4.82 ± 2.23 pmol/L) correlated positively with N-terminal propeptide of type 1 collagen (r = 0.56, p < 0.05). Mid-cycle E2 levels presented significant negative association with the percent decrease of C-telopeptide of collagen cross-links at all-time points during the luteal period (r = -0.60 to -0.68, p < 0.05-0.01). Circulating sclerostin and Dickkopf-1 levels do not change across the menstrual cycle and do not demonstrate any relationship with estradiol in premenopausal women. Further investigation is needed concerning the role of sclerostin and Dickkopf-1 on bone turnover in young estrogen-sufficient women.

SOST Inhibits Prostate Cancer Invasion.

Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings.