title: Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure.
abstract: BACKGROUND
  Resistance to the action of parathyroid hormone (PTH) has been demonstrated in end-stage renal failure and is considered to be important in the pathogenesis of secondary hyperparathyroidism. The mechanism of resistance is unknown. However, altered regulation of cellular PTH/PTH-related protein (PTH/PTHrP) receptor (PTH1R) has been assumed to be important.
  
  
  METHODS
  We have used in situ hybridization to examine PTH1R mRNA expression by osteoblasts in human bone and have compared the expression in high- and low-turnover renal bone disease, high-turnover nonrenal bone disease (healing fracture callus and Pagetic bone), and normal bone. Bone biopsies were formalin fixed, ethylenediaminetetraacetic acid decalcified, and paraffin wax embedded. A 1.8 kb PTH1R cDNA probe, labeled with 35S, was used, and the hybridization signal was revealed by autoradiography. The density of signal over osteoblasts was quantitated using a semiautomated Leica image analysis software package.
  
  
  RESULTS
  The mean density of PTH1R mRNA signal over osteoblasts in renal high-turnover bone was only 36% of that found in nonrenal high-turnover bone (P < 0.05) and 51% of that found in normal bone (P < 0.05). Osteoblast PTH1R mRNA signal in adynamic bone from individuals with diabetes mellitus was 28% of normal bone (P < 0.05) and 54% of that found in renal high-turnover bone (P < 0.05).
  
  
  CONCLUSIONS
  These results demonstrate a down-regulation of osteoblast PTH1R mRNA in end-stage renal failure in comparison to normal and high-turnover bone from otherwise healthy individuals, and provide an insight into the mechanisms of "skeletal resistance" to the actions of PTH.
authors.affiliation: Musculoskeletal Research Group, School of Medicine, University of Manchester, and Renal Unit, Manchester Royal Infirmary, Manchester, England, United Kingdom.
authors.forename: M L
authors.initials: ML
authors.lastname: Picton
authors.forename: P R
authors.initials: PR
authors.lastname: Moore
authors.forename: E B
authors.initials: EB
authors.lastname: Mawer
authors.forename: D
authors.initials: D
authors.lastname: Houghton
authors.forename: A J
authors.initials: AJ
authors.lastname: Freemont
authors.forename: A J
authors.initials: AJ
authors.lastname: Hutchison
authors.forename: R
authors.initials: R
authors.lastname: Gokal
authors.forename: J A
authors.initials: JA
authors.lastname: Hoyland
mesh_terms: D000328:Adult; D001842:Bone and Bones / Q000378:metabolism; D002146:Bony Callus / Q000378:metabolism / Q000503:physiopathology; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D017403:In Situ Hybridization; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010001:Osteitis Deformans / Q000378:metabolism / Q000503:physiopathology; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000235:genetics* / Q000378:metabolism; D014511:Uremia / Q000378:metabolism / Q000503:physiopathology
chemical_list: D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone