Gene expression analysis in human osteoblasts exposed to dexamethasone identifies altered developmental pathways as putative drivers of osteoporosis.
BACKGROUND
Osteoporosis, a disease of decreased bone mineral density represents a significant and growing burden in the western world. Aging population structure and therapeutic use of glucocorticoids have contributed in no small way to the increase in the incidence of this disease. Despite substantial investigative efforts over the last number of years the exact molecular mechanism underpinning the initiation and progression of osteoporosis remain to be elucidated. This has meant that no significant advances in therapeutic strategies have emerged, with joint replacement surgery being the mainstay of treatment.


METHODS
In this study we have used an integrated genomics profiling and computational biology based strategy to identify the key osteoblast genes and gene clusters whose expression is altered in response to dexamethasone exposure. Primary human osteoblasts were exposed to dexamethasone in vitro and microarray based transcriptome profiling completed.


RESULTS
These studies identified approximately 500 osteoblast genes whose expression was altered. Functional characterization of the transcriptome identified developmental networks as being reactivated with 106 development associated genes found to be differentially regulated. Pathway reconstruction revealed coordinate alteration of members of the WNT signaling pathway, including frizzled-2, frizzled-7, DKK1 and WNT5B, whose differential expression in this setting was confirmed by real time PCR.


CONCLUSIONS
The WNT pathway is a key regulator of skeletogenesis as well as differentiation of bone cells. Reactivation of this pathway may lead to altered osteoblast activity resulting in decreased bone mineral density, the pathological hallmark of osteoporosis. The data herein lend weight to the hypothesis that alterations in developmental pathways drive the initiation and progression of osteoporosis.
Hurson
Conor J
CJ
General Clinical Research Unit, School of Medicine and Medical Sciences, University College Dublin, Mater Misericordiae University Hospital and Dublin Molecular Medicine Centre, Dublin, Ireland. conorhurson@hotmail.com <conorhurson@hotmail.com>
Butler
Joseph S
JS
Keating
Dominic T
DT
Murray
David W
DW
Sadlier
Denise M
DM
O'Byrne
John M
JM
Doran
Peter P
PP
D017209:Apoptosis / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000009:adverse effects*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000187:drug effects*; D010024:Osteoporosis / Q000209:etiology*; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000187:drug effects
D005938:Glucocorticoids; D051153:Wnt Proteins; D003907:Dexamethasone