osteoprotegerin and Cushing-Syndrome

Patients with endogenous hypercortisolism have higher sclerostin, but do not differ in Dickkopf 1 (Dkk1) or secreted frizzled-related protein 1 (SFRP1) levels as compared to healthy control.. Endogenous Cushing's syndrome (CS), usually affecting young and otherwise healthy patients, is a good model to validate the effects of supraphysiological levels of glucocorticoids in humans. This study evaluates circulating levels of extracellular antagonists of the Wnt/β-catenin signaling pathway (sclerostin, Dkk1, SFRP1) in patients with CS versus healthy individuals.. Forty patients with clinically and biochemically evident CS and 40 sex-, age-, and body mass index-matched healthy subjects provided fasting serum samples for sclerostin, SFRP1 and Dkk1, along with bone turnover markers.. Patients with CS had higher sclerostin levels (34.5 (30.3-37.1) pmol/L) versus healthy individuals (29.9 (24.3-36.8) pmol/L) (p = 0.032). Differences in sclerostin were due to the lack of lower sclerostin values rather than an increase in protein levels above the upper limits of the healthy control. The odds of sclerostin levels being higher than 30 pmol/L were greater in patients with CS as compared with the odds in healthy subjects (odds ratio = 3.81 95 % confidence interval 1.45-10.02) (p = 0.01). It coexisted with suppressed bone formation and unchanged bone resorption markers. Dkk1, SFRP1 did not differ from the control group.. Of all the tested proteins (sclerostin, Dkk1, SFRP1), only sclerostin showed a significant difference when contrasting CS with healthy subjects. Hypercortisolism might prevent the down-regulation of sclerostin. Targeting sclerostin seems to be a promising therapeutic approach to treating osteoporosis in patients with CS.

Topics: Adaptor Proteins, Signal Transducing; Adult; Biomarkers; Bone Density; Bone Morphogenetic Proteins; Case-Control Studies; Cushing Syndrome; Female; Femur Neck; Genetic Markers; Humans; Intercellular Signaling Peptides and Proteins; Lumbar Vertebrae; Male; Membrane Proteins; Middle Aged; Osteogenesis; Osteoporotic Fractures; Osteoprotegerin; RANK Ligand; Wnt Signaling Pathway; Young Adult

Patients with endogenous Cushing's Syndrome (CS), as long-time treated patients with exogenous glucocorticoids (GCs), have severe systemic manifestations including secondary osteoporosis and low-energy fractures. The aim of the present study was to investigate the functional role of TXNIP in bone with focus on osteoblast (OB) differentiation and OB-mediated osteoclast activity and function in vitro.. Nine bone biopsies from CS before and after surgical treatment were screened for expressional candidate genes. Microarray analyses revealed that the gene encoding TXNIP ranked among the most upregulated genes. Subsequent in vitro and in vivo studies were performed.. We found that TXNIP gene in bone is downregulated in CS following surgical treatment. Furthermore, our in vivo data indicate novel associations between thioredoxin and TXNIP. Our in vitro studies showed that silencing TXNIP in OBs was followed by increased differentiation and expression and secretion of osteocalcin as well as enhanced activity of alkaline phosphatase. Moreover, treating osteoclasts with silenced TXNIP OB media showed an increased osteoclast activity.. TXNIP expression in bone is highly regulated during the treatment of active CS, and by GC in bone cells in vitro. Our data indicate that TXNIP may mediate some of the detrimental effects of GC on OB function as well as modulate OB-mediated osteoclastogenesis by regulating the OPG/RANKL ratio.

Topics: Adult; Aged; Biopsy; Bone and Bones; Bone Remodeling; Carrier Proteins; Cushing Syndrome; Down-Regulation; Female; Gene Silencing; Glucocorticoids; Humans; Male; Middle Aged; Osteoblasts; Osteoclasts; Osteoprotegerin; Protein Array Analysis; RANK Ligand

Osteoprotegerin (OPG) has been identified as a decoy receptor that inhibits osteoclast differentiation and, more recently, as a paracrine regulator of vascular calcification. OPG is suppressed by glucocorticoids (GC); however, results from experimental and clinical studies are not univocal. The aim of this study was to evaluate OPG and bone metabolism in patients with Cushing's syndrome (CS) before and after cure.. Twenty-six patients with CS (all women, mean age: 39.1+/-11.9 years) and 24 age- and gonadal status-matched healthy women were studied for bone mineral density, bone metabolism, OPG, and receptor activator of nuclear factor-kB ligand at baseline. Twelve patients were also studied 6-18 months after surgery, with persistent normalization of cortisol levels.. OPG was significantly higher and osteocalcin (OC) was significantly lower in CS patients than in controls (OPG: 4.17+/-1.23 vs 2.95+/-0.79 pmol/l, P=0.00001; OC: 15.0+/-6.1 vs 18.8+/-6.8 ng/ml, P=0.04 in CS and controls respectively). After cure, we found no difference in OPG levels, despite a significant increase in OC levels (from 16.4+/-11 to 37.2+/-15 ng/ml, P=0.03).. Patients with CS showed increased OPG serum levels that remained unchanged after recovery, despite a restoration of bone formation. We speculate that high levels of OPG could reflect the persistent damage of the GCs on cardiovascular system.

Topics: Adolescent; Adult; Aged; Bone Density; Cushing Syndrome; Female; Humans; Hydrocortisone; Longitudinal Studies; Middle Aged; Osteoprotegerin; Retrospective Studies; Young Adult

Patients with Cushing's syndrome (CS) have a mortality rate four times higher than age- and sex-matched subjects, mainly due to cardiovascular events. Serum osteoprotegerin (OPG) levels are increased in patients with cardiovascular disease and/or excess bone resorption.. The aim of the study was to assess serum OPG and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) levels in CS and their possible relationship with coronary risk profile.. We conducted a cross-sectional study at a tertiary referral center.. We studied 48 adult patients with CS and 48 age- and sex-matched controls. Twenty-six patients had pituitary-dependent CS; five patients had CS caused by ectopic ACTH secretion; and 17 patients had adrenal-dependent CS, accounted for by cortisol-secreting adenoma (n = 9), ACTH-independent macronodular bilateral adrenal hyperplasia (n = 4), or World Health Organization stage II cortisol-secreting carcinoma (n = 4). Patients underwent assessment of the absolute coronary risk and measurement of bone mineral density by dual-energy x-ray absorptiometry. Serum OPG and total sRANKL were measured by ELISA.. Serum OPG (but not sRANKL) levels were significantly higher in CS patients than in controls (P < 0.01). In patients, serum OPG showed a positive correlation with age (r = 0.36; P = 0.01). OPG levels were higher in patients with the metabolic syndrome [median, 1262 (range, 199-2306) pg/ml vs. 867 (412-2479) pg/ml; P = 0.03], and showed a positive correlation with the absolute coronary risk (r = 0.36; P = 0.01). Serum OPG levels were higher in patients with pituitary-dependent CS in comparison with adrenal-dependent CS.. In patients with CS, serum OPG levels are increased and appear to be associated with coronary risk.

Topics: Absorptiometry, Photon; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Aged; Cardiovascular Diseases; Cross-Sectional Studies; Cushing Syndrome; Female; Humans; Hydrocortisone; Male; Metabolic Syndrome; Middle Aged; Osteoprotegerin; Pituitary Function Tests; Pituitary Gland; Receptor Activator of Nuclear Factor-kappa B; Risk

To investigate the possible role of osteoprotegerin (OPG) in bone metabolism in humans by measuring serum levels of OPG in five well-characterized patient populations with known or suspected pathology in bone homeostasis, but with differences in the pathogenesis of these disturbances.. The study comprised 34 patients with Cushing's syndrome (CS), 24 acromegalic patients, 16 patients with growth hormone deficiency (GHD), 29 HIV-infected patients, 25 patients with common variable immunodeficiency (CVI) and 59 age- and sex-matched healthy controls (CTR).. Serum levels of tumor necrosis factor (TNF)-alpha, OPG, C-terminal telopeptides of Type-I collagen (CTX-I) and osteocalcin were determined in all study subjects as well as cortisol (CS and CTR) and IGF-I (acromegaly, GHD and CTR).. OPG levels were significantly elevated in both CVI (median increase approximately 32%, P < 0.05) and HIV-infected patients with especially high levels in the latter group ( approximately 52%, P < 0.001), significantly correlated with increased TNFalpha levels (r = 0.47, P < 0.02). Also CS patients had elevated serum OPG ( approximately 24%, P < 0.01), significantly correlated with increased serum cortisol (r = 0.35, P < 0.05). In contrast, OPG levels in acromegalic and GHD patients were not different from healthy controls. No relationships were found between OPG levels and CTX-I or osteocalcin.. These findings suggest that enhanced OPG levels may be a compensatory response to enhanced osteoclast activity or negative bone remodeling balance in some conditions, but may also be a parameter of enhanced activity in the OPG system possibly correlated to enhanced activity of other members of the TNF family.

Topics: Acromegaly; Adult; Aged; Bone and Bones; Bone Remodeling; Common Variable Immunodeficiency; Cushing Syndrome; Female; Glucocorticoids; Glycoproteins; HIV Infections; Homeostasis; Human Growth Hormone; Humans; Hydrocortisone; Immunologic Deficiency Syndromes; Insulin-Like Growth Factor I; Male; Middle Aged; Osteocalcin; Osteoclasts; Osteoprotegerin; Peptide Fragments; Procollagen; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha