title: Gene expression profiles give insight into the molecular pathology of bone in primary hyperparathyroidism.
abstract: Global gene expression profiling has been used to study the molecular mechanisms of increased bone remodeling caused by PHPT. This disease is a model for chronic over-stimulation of target organs by PTH due to an inappropriate overproduction of the hormone. Hyperactivity of osteoblasts and osteoclasts lead to increased calcium and phosphate mobilization from the skeleton and hypercalcaemia. The ensemble of genes that alter expression and thus is responsible for the effects of chronic PTH stimulation is today largely unknown. The differentiated gene expression profiles revealed characteristic molecular disease modalities which define the bone remodeling abnormalities occurring in PTH dependent osteodystrophy. We analyzed mRNAs in transiliacal bone biopsies from 7 patients with PHPT using Affymetrix HG-U133A Gene Chips containing more than 22000 different probe sets. Similar analyses of the global transcriptional activity were repeated in a second bone biopsy from the same patient taken one year after surgery and reversal of disease parameters. Real time PCR was carried out on many genes for corroboration of the results. Out of more than 14500 different genes examined, 99 which were related to bone and extra-cellular matrix, showed altered expression. Of these were 85 up- and 14 down-regulated before operation. The majority of regulated genes represented structural and adhesion proteins, but included also proteases and protease regulators which promote resorption. Increased expressions of collagen type 1 and osteocalcin mRNAs in disease reflecting the PTH anabolic action were paralleled by increased concentrations of these proteins in serum. In addition, genes encoding transcriptional factors and their regulators as well as cellular signal molecules were up-regulated during disease. The identified genetic signature represents the first extensive description of the ensemble of bone and matrix related mRNAs, which are regulated by chronic PTH action. These results identify the molecular basis for this skeletal disease, and provide new insight into this clinical condition with potential bearing on future treatment.
authors.affiliation: University of Oslo, Department of Medical Biochemistry, P.O. Box 1112 Blindern, 0317 Oslo, Norway, and Department of Endocrinology, Odense University Hospital, Denmark. sjur.repe@basalmed.uio.no
authors.forename: Sjur
authors.initials: S
authors.lastname: Reppe
authors.forename: Lis
authors.initials: L
authors.lastname: Stilgren
authors.forename: Ole K
authors.initials: OK
authors.lastname: Olstad
authors.forename: Kim
authors.initials: K
authors.lastname: Brixen
authors.forename: Lise Sofie
authors.initials: LS
authors.lastname: Nissen-Meyer
authors.forename: Kaare M
authors.initials: KM
authors.lastname: Gautvik
authors.forename: Bo
authors.initials: B
authors.lastname: Abrahamsen
mesh_terms: D015502:Absorptiometry, Photon; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D015342:DNA Probes; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000378:metabolism / Q000503:physiopathology*; D007085:Ilium / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D013997:Time Factors
chemical_list: D015415:Biomarkers; D015342:DNA Probes; D012333:RNA, Messenger; D002118:Calcium