title: TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing's syndrome and related to bone turnover.
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.
  
  
  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.
authors.affiliation: Section of Specialized Endocrinology, Department of Endocrinology, Faculty of Medicine, University of Oslo and Oslo University Hospital, 0027 Oslo, Norway. tove.lekva@medisin.uio.no
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Hege
authors.initials: H
authors.lastname: Bøyum
authors.forename: Johan Arild
authors.initials: JA
authors.lastname: Evang
authors.forename: Kristin
authors.initials: K
authors.lastname: Godang
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D003480:Cushing Syndrome / Q000235:genetics / Q000378:metabolism* / Q000601:surgery*; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D005938:Glucocorticoids / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism; D040081:Protein Array Analysis; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D005938:Glucocorticoids; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C486715:TXNIP protein, human