The relationship between inhibitors of the Wnt signalling pathway (sclerostin and Dickkopf-1) and carotid intima-media thickness in postmenopausal women with type 2 diabetes mellitus.

The aim of the study was to investigate the association of the extracellular inhibitors of Wnt/ß-catenin signalling sclerostin and Dickkopf-1 (Dkk-1) with carotid intima-media thickness (CIMT) in type 2 diabetes mellitus (T2DM). We performed a cross-sectional study including 40 T2DM postmenopausal women and 40 healthy controls. CIMT was measured by B-mode ultrasound. Serum sclerostin and Dkk-1 were measured by solid-phase enzyme-linked immunosorbent assay (ELISA). Serum sclerostin and Dkk-1 concentrations were significantly higher in T2DM group than in controls. There was a significant negative correlation between sclerostin and Dkk-1 and CIMT in T2DM (p = 0.0063 and p = 0.0017, respectively). After adjustment for potential confounders, associations remained significant only for sclerostin. These data suggest that sclerostin, an established modulator of the canonical Wnt signalling, may protect against progression of vascular complications in diabetic patients, possibly by attenuating upregulation of ß-catenin activity in the vascular cells.

Sclerostin levels associated with inhibition of the Wnt/ß-catenin signaling and reduced bone turnover in type 2 diabetes mellitus.

CONTEXT: Patients with type 2 diabetes (T2DM) have low bone turnover, poor bone quality, and circulating levels of sclerostin significantly higher than non-T2DM controls. There are no data on the possible association of sclerostin with ß-catenin, a key component of the Wnt/ß-catenin canonical signaling. OBJECTIVES: The aim of the study was to evaluate the circulating ß-catenin levels in T2DM patients and to analyze their relationship with sclerostin and bone turnover markers. DESIGN: This was a cross-sectional study. SETTING AND PATIENTS: The study was conducted at a clinical research center. Forty T2DM postmenopausal women were studied and compared with 40 healthy controls. Bone status was assessed by dual-energy x-ray absorptiometry measurements (bone mineral density) and by measuring bone alkaline phosphatase and carboxy-terminal telopeptide of type 1 collagen. Sclerostin and ß-catenin were evaluated by an immunoenzymetric assay. RESULTS: Consistent with previous reports in T2DM subjects, we found sclerostin levels higher and bone turnover markers lower than controls. In our cohort of T2DM patients, ß-catenin levels are significantly lower than in controls (median 1.22 pg/ml, 25th to 75th percentiles 0.50-2.80; and median 4.25 pg/ml, 25th to 75th percentiles 2.20-7.62, respectively; P=0.0002). ß-Catenin correlated negatively with sclerostin (P<0.0001) and positively with bone alkaline phosphatase (P=0.0030) only in T2DM patients and negatively with age in both groups. Eight of the 40 T2DM patients had vertebral fractures. CONCLUSIONS: These results show for the first time that T2DM patients have serum concentrations of ß-catenin lower than controls. The negative association of ß-catenin with sclerostin suggests a biological effect of increased sclerostin on the Wnt signaling, which appears impaired in T2DM.

Reduction of volumetric bone mineral density in postmenopausal women with hepatitis C virus-correlated chronic liver disease: a peripheral quantitative computed tomography (pQCT) study.

BACKGROUND: The prevalence of osteoporosis in chronic liver disease (CLD) varies considerably among the studies, depending on patient selection and diagnostic criteria. We aimed to measure bone turnover markers and volumetric bone mineral density (BMD) in a group of postmenopausal women with CLD using both dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), in comparison with age-matched healthy subjects. METHODS: Thirty-five postmenopausal patients with HCV-correlated CLD and 35 healthy postmenopausal women, as controls, underwent a DXA scan at lumbar and femoral level and a pQCT measurement of the nondominant forearm. Serum concentrations of biochemical markers relevant to bone turnover were also measured. RESULTS: Patients showed no differences in DXA values either at lumbar or femoral level compared to controls. On the contrary, pQCT geometrical (cortical cross-sectional area) and volumetric (total and trabecular volumetric BMD) parameters were significantly reduced in the CLD women. Also the Strength-Strain Index (SSI), an estimate of diaphyseal bone resistance to bending and torsion, was significantly lower in patients than in controls. Patients with CLD presented an unbalanced bone turnover, with increased bone resorption markers. CONCLUSIONS: The bone geometrical and volumetric parameters measured in our CLD postmenopausal women, by pQCT, show a reduced bone mineral quality and stiffness. Conversely, DXA-measurements seem unable to appreciate the bone alterations in these patients. This would encourage further studies to validate pQCT analysis as a diagnostic tool for a correct estimate of bone involvement in CLD.

Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss.

CONTEXT: Sclerostin, a Wnt signaling antagonist on the osteoblasts produced by osteocytes, is regulated by mechanical strain and is implicated in the pathogenesis of disuse bone loss. There are no data on sclerostin in humans. OBJECTIVE: The aim of the study was to evaluate sclerostin in patients immobilized after stroke, compared with control subjects, and to analyze its relationship with markers of bone formation and resorption. DESIGN: This was a cross-sectional study. SETTING AND PATIENTS: We studied 40 postmenopausal women immobilized after a single episode of stroke 6 months or longer after onset, and 40 postmenopausal women from the general community. Bone status was assessed by quantitative ultrasound measurements at the calcaneus. Bone alkaline phosphatase (b-AP), carboxy-terminal telopeptide of type I collagen (CrossLaps), and sclerostin were evaluated by ELISA. We also used ELISA to measure serum levels of Dickkopf-1, another soluble inhibitor of Wnt/beta-catenin signaling, highly expressed by osteocytes. RESULTS: Immobilized patients had higher sclerostin serum levels (median 0.975 ng/ml; 25th to 75th percentiles 0.662-1.490) than controls (median 0.300 ng/ml; 25th to 75th percentiles 0.165-0.400: P < 0.0001) and an increased bone turnover with a more significant rise in bone resorption (CrossLaps) than formation (b-AP) markers. Sclerostin correlated negatively with b-AP (r = -0.911; P < 0.0001) and positively with CrossLaps (r = 0.391; P = 0.012). Dickkopf-1 did not significantly differ between the groups. Patients also had quantitative ultrasound measurements index lower than controls (P < 0.001). CONCLUSIONS: This study shows for the first time that long-term immobilized patients present hypersclerostinemia associated with reduced bone formation, and suggests that sclerostin could be a link between mechanical unloading and disuse osteoporosis in humans.