title: Molecular disease map of bone characterizing the postmenopausal osteoporosis phenotype.
abstract: Genome-wide gene expressions in bone biopsies from patients with postmenopausal osteoporosis and healthy controls were profiled, to identify osteoporosis candidate genes. All osteoporotic patients (n = 27) in an unbiased cohort of Norwegian women presented with bone mineral density (BMD) T-scores of less than -2.5 SD and one or more confirmed low-energy fracture(s). A validation group (n = 18) had clinical and laboratory parameters intermediate to the control (n = 39) and osteoporosis groups. RNA from iliac crest bone biopsies were analyzed by Affymetrix microarrays and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Differentially expressed genes in osteoporosis versus control groups were identified using the Bayesian ANOVA for microarrays (BAMarray) method, whereas the R-package Limma (Linear Models for Microarray Data) was used to determine whether these transcripts were explained by disease, age, body mass index (BMI), or combinations thereof. Laboratory tests showed normal ranges for the cohort. A total of 609 transcripts were differentially expressed in osteoporotic patients relative to controls; 256 transcripts were confirmed for disease when controlling for age or BMI. Most of the osteoporosis susceptibility genes (80%) also were confirmed to be regulated in the same direction in the validation group. Furthermore, 217 of 256 transcripts were correlated with BMD (adjusted for age and BMI) at various skeletal sites (|r| > 0.2, p < .05). Among the most distinctly expressed genes were Wnt antagonists DKK1 and SOST, the transcription factor SOX4, and the bone matrix proteins MMP13 and MEPE, all reduced in osteoporosis versus control groups. Our results identify potential osteoporosis susceptibility candidate genes adjusted for confounding factors (ie, age and BMI) with or without a significant correlation with BMD.
authors: Section of Endocrinology, Department of Medicine, Rikshospitalet University Hospital, Oslo, Norway.
authors: Rune
authors: R
authors: Jemtland
authors: Marit
authors: M
authors: Holden
authors: Sjur
authors: S
authors: Reppe
authors: Ole K
authors: OK
authors: Olstad
authors: Finn P
authors: FP
authors: Reinholt
authors: Vigdis T
authors: VT
authors: Gautvik
authors: Hilde
authors: H
authors: Refvem
authors: Arnoldo
authors: A
authors: Frigessi
authors: Brian
authors: B
authors: Houston
authors: Kaare M
authors: KM
authors: Gautvik
mesh_terms: D000375:Aging / Q000235:genetics; D001706:Biopsy; D015992:Body Mass Index; D015519:Bone Density / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D008019:Life Style; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015663:Osteoporosis, Postmenopausal / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction