Serum extracellular secreted antagonists of the canonical Wnt/β-catenin signaling pathway in patients with Cushing’s syndrome

Belaya, Zhanna; Rozhinskaya, Ludmila; Мельниченко, Г. А.; Solodovnikov, Alexander; Dragunova, N V; Iljin, Alexander V.; Dzeranova, Larisa; Dedov, Ivan I.

doi:10.1007/s00198-013-2268-y

Cited by 41 publications

(27 citation statements)

References 40 publications

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“…Yet another study described that sclerostin levels were decreased in patients with endogenous hypercortisolism, and increased after correction [21]. In contrast, Belaya et al reported recently high sclerostin values in patients with Cushing's syndrome [22]. Although it is tempting to speculate that the high steroid dosage immediately after transplantation might have contributed to the rapid decrease of the sclerostin levels, this requires further studies.…”

Section: Discussionmentioning

confidence: 89%

Sclerostin Blood Levels Before and After Kidney Transplantation

Bonani

Rodríguez

Fehr

et al. 2014

Kidney Blood Press Res

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Background/Aims: Sclerostin is secreted by osteocytes. As a circulating inhibitor of the Wnt-signaling pathway it inhibits bone formation and contributes to the development of osteoporosis. Sclerostin levels are elevated in patients with chronic kidney disease and end-stage renal disease. Since data for patients after kidney transplantation are scarce, we have prospectively measured sclerostin levels before and during the first year after renal transplantation and have examined the association of sclerostin with parameters of bone mineral metabolism and with bone mineral density. Methods: Sclerostin levels were measured by ELISA in 42 consecutive renal transplant recipients before and at defined intervals in the first year after transplantation. Bone mineral density was measured by dual energy X-ray absorptiometry. Results: Pre-transplant serum sclerostin levels were elevated in all patients (61.8 ± 32.3 pmol/l, normal range 20-30 pmol/l). Within 15 days after transplantation and correlating with the improvement of renal function, sclerostin levels dropped to 21.0 ± 14.7 pmol/l and subsequently increased to 23.8 ± 14.9 and 28.0 ± 16.8 pmol/l after 6 and 12 months, respectively (P<0.001). A linear mixed model indicated that pre-transplant sclerostin levels (P<0.001) and time after transplantation (P<0.001) were the most important predictors for the rise of post-transplant sclerostin levels. No correlation was found between post-transplant sclerostin levels and bone mineral density. Conclusions: The rapid reduction of elevated serum sclerostin levels shortly after kidney transplantation parallels the improvement of renal function, but contrasts with the more delayed improvement of hyperparathyroidism. The normalization of both hormones could contribute to improved bone health after renal transplantation.

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Section: Discussionmentioning

confidence: 89%

Sclerostin Blood Levels Before and After Kidney Transplantation

Bonani

Rodríguez

Fehr

et al. 2014

Kidney Blood Press Res

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“…34–38 Yet, the evidence for a substantial link in human patients has been discordant with decreased serum sclerostin at one week in GC patients, 39 and increased serum sclerostin at later time points. 40 Similar disparities are seen with sclerostin and disease states: increased levels are reported in Cushing’s syndrome patients, 41 whereas cases of chronic hypercortisolism presented with decreased sclerostin. 42 Sclerostin activity as a means for heavy metals to facilitate osteoporotic bone loss was first established in animal systems 19,43–45 and their association was recently revealed in osteoporotic patients.…”

Section: Introductionmentioning

confidence: 79%

Sclerostin activity plays a key role in the negative effect of glucocorticoid signaling on osteoblast function in mice

et al. 2017

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Stress during prenatal development is correlated with detrimental cognitive and behavioral outcomes in offspring. However, the long-term impact of prenatal stress (PS) and disrupted glucocorticoid signaling on bone mass and strength is not understood. In contrast, the detrimental effect of lead (Pb) on skeletal health is well documented. As stress and Pb act on common biological targets via glucocorticoid signaling pathways and co-occur in the environment, this study first sought to assess the combined effect of stress and Pb on bone quality in association with alterations in glucocorticoid signaling. Bone parameters were evaluated using microCT, histomorphometry, and strength determination in 8-month-old male mouse offspring subjected to PS on gestational days 16 and 17, lifetime Pb exposure (100 p.p.m. Pb in drinking water), or to both. Pb reduced trabecular bone mass and, when combined with PS, Pb unmasked an exaggerated decrement in bone mass and tensile strength. Next, to characterize a mechanism of glucocorticoid effect on bone, prednisolone was implanted subcutaneously (controlled-release pellet, 5 mg·kg−1 per day) in 5-month-old mice that decreased osteoblastic activity and increased sclerostin and leptin levels. Furthermore, the synthetic glucocorticoid dexamethasone alters the anabolic Wnt signaling pathway. The Wnt pathway inhibitor sclerostin has several glucocorticoid response elements, and dexamethasone administration to osteoblastic cells induces sclerostin expression. Dexamethasone treatment of isolated bone marrow cells decreased bone nodule formation, whereas removal of sclerostin protected against this decrement in mineralization. Collectively, these findings suggest that bone loss associated with steroid-induced osteoporosis is a consequence of sclerostin-mediated restriction of Wnt signaling, which may mechanistically facilitate glucocorticoid toxicity in bone.

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“…However, its significance in the development of glucocorticoid-induced bone loss is not completely clear. Recently, higher levels of sclerostin, an extra-cellular antagonist of the Wingless/β-catenin (Wnt) signaling pathway, were noted in patients with Cushing’s syndrome compared to healthy individuals (22). However contradictory results were found in another study (266).…”

Section: Clinical Features Of Cushing’s Syndromementioning

confidence: 99%

Physiological Basis for the Etiology, Diagnosis, and Treatment of Adrenal Disorders: Cushing's Syndrome, Adrenal Insufficiency, and Congenital Adrenal Hyperplasia

Raff

Sharma

Nieman

2014

Comprehensive Physiology

122

105

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The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing’s syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing’s syndrome). Endogenous Cushing’s syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing’s syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control.

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Serum extracellular secreted antagonists of the canonical Wnt/β-catenin signaling pathway in patients with Cushing’s syndrome

Cited by 41 publications

References 40 publications

Sclerostin Blood Levels Before and After Kidney Transplantation

Sclerostin Blood Levels Before and After Kidney Transplantation

Sclerostin activity plays a key role in the negative effect of glucocorticoid signaling on osteoblast function in mice

Physiological Basis for the Etiology, Diagnosis, and Treatment of Adrenal Disorders: Cushing's Syndrome, Adrenal Insufficiency, and Congenital Adrenal Hyperplasia

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