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1.
PLoS One ; 8(5): e64247, 2013.
Article in English | MEDLINE | ID: mdl-23691179

ABSTRACT

Recent studies have described bone as an endocrine organ regulating glucose metabolism, with insulin signaling regulating osteocalcin secretion and osteocalcin regulating ß cell function. We have previously demonstrated increased bone expression of TXNIP in patients with endogenous Cushing's syndrome (CS), and we hypothesized that TXNIP could contribute to the dysregulated glucose metabolism in CS. We studied 33 CS patients and 29 matched controls, with bone biopsies from nine patients, before and after surgical treatment. In vitro, the effect of silencing TXNIP (siTXNIP) in osteoblasts, including its effect on human islet cells, was examined. Our major findings were: (i) The high mRNA levels of TXNIP in bone from CS patients were significantly associated with high levels of glucose and insulin, increased insulin resistance, and decreased insulin sensitivity in these patients. (ii) Silencing TXNIP in osteoblasts enhanced their OC response to insulin and glucose and down-regulated interleukin (IL)-8 levels in these cells. (iii) Conditional media from siTXNIP-treated osteoblasts promoted insulin content and anti-inflammatory responses in human islet cells. We recently demonstrated that the thioredoxin/TXNIP axis may mediate some detrimental effects of glucocorticoid excess on bone tissue in CS. Here we show that alterations in this axis also may affect glucose metabolism in these patients.


Subject(s)
Bone and Bones/metabolism , Carrier Proteins/metabolism , Energy Metabolism/physiology , Glucose/metabolism , Homeostasis/physiology , Analysis of Variance , Blotting, Western , Cushing Syndrome , DNA Primers/genetics , Gene Silencing , Humans , Insulin/metabolism , Insulin Resistance/physiology , Interleukin-8/metabolism , Islets of Langerhans/metabolism , Microarray Analysis , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction
2.
Eur J Endocrinol ; 166(6): 1039-48, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22450549

ABSTRACT

OBJECTIVE: 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. DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
Bone Remodeling , Bone and Bones/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cushing Syndrome/metabolism , Cushing Syndrome/surgery , Glucocorticoids/adverse effects , Osteoblasts/metabolism , Osteoclasts/metabolism , Adult , Aged , Biopsy , Cushing Syndrome/genetics , Down-Regulation , Female , Gene Silencing , Glucocorticoids/metabolism , Humans , Male , Middle Aged , Osteoprotegerin/metabolism , Protein Array Analysis , RANK Ligand/metabolism
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