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


BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
The National Research Center for Endocrinology, ul. Dmitria Uljanova, 11, Moscow 117036, Russia. jannabelaya@gmail.com
Z E
ZE
Belaya
L Y
LY
Rozhinskaya
G A
GA
Melnichenko
A G
AG
Solodovnikov
N V
NV
Dragunova
A V
AV
Iljin
L K
LK
Dzeranova
I I
II
Dedov
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000502:physiology; D016022:Case-Control Studies; D003480:Cushing Syndrome / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D005260:Female; D005272:Femur Neck / Q000503:physiopathology; D005819:Genetic Markers / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000502:physiology; D008159:Lumbar Vertebrae / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000502:physiology; D008875:Middle Aged; D010012:Osteogenesis / Q000502:physiology; D058866:Osteoporotic Fractures / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D053244:Osteoprotegerin / Q000097:blood; D053245:RANK Ligand / Q000097:blood; D060449:Wnt Signaling Pathway / Q000502:physiology*; D055815:Young Adult; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; C501126:DKK1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C422903:SOST protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human