Gene expression profile of the bone microenvironment in human fragility fracture bone.

ABSTRACT

Osteoporosis (OP) is a common age-related systemic skeletal disease, with a strong genetic component, characterised by loss of bone mass and strength, which leads to increased bone fragility and susceptibility to fracture. Although some progress has been made in identifying genes that may contribute to OP disease, much of the genetic component of OP has yet to be accounted for. Therefore, to investigate the molecular basis for the changes in bone causally involved in OP and fragility fracture, we have used a microarray approach. We have analysed altered gene expression in human OP fracture bone by comparing mRNA in bone from individuals with fracture of the neck of the proximal femur (OP) with that from age-matched individuals with osteoarthritis (OA), and control (CTL) individuals with no known bone pathology. The OA sample set was included because an inverse association, with respect to bone density, has been reported between OA and the OP individuals. Compugen H19K oligo human microarray slides were used to compare the gene expression profiles of three sets of female samples comprising, 10 OP-CTL, 10 OP-OA, and 10 OA-CTL sample pairs. Using linear models for microarray analysis (Limma), 150 differentially expressed genes in OP bone with t scores >5 were identified. Differential expression of 32 genes in OP bone was confirmed by real time PCR analysis (p<0.01). Many of the genes identified have known or suspected roles in bone metabolism and in some cases have been implicated previously in OP pathogenesis. Three major sets of differentially expressed genes in OP bone were identified with known or suspected roles in either osteoblast maturation (PRRX1, ANXA2, ST14, CTSB, SPARC, FST, LGALS1, SPP1, ADM, and COL4A1), myelomonocytic differentiation and osteoclastogenesis (TREM2, ANXA2, IL10, CD14, CCR1, ADAM9, CCL2, CTGF, and KLF10), or adipogenesis, lipid and/or glucose metabolism (IL10, MARCO, CD14, AEBP1, FST, CCL2, CTGF, SLC14A1, ANGPTL4, ADM, TAZ, PEA15, and DOK4). Altered expression of these genes and others in these groups is consistent with previously suggested underlying molecular mechanisms for OP that include altered osteoblast and osteoclast differentiation and function, and an imbalance between osteoblastogenesis and adipogenesis.