Figure 5: Dexamethasone elicited alterations in developmental gene expression. Confirmation of the microarray identified alterations in expression of DKK1, frizzled 2, frizzled 7 and WNT5B (Panels A, B, C and D respectively.) by quantitative real time PCR. All expression values were normalised to 18S rRNA. All measurements were completed in triplicate. Data are quoted relative to control. (* P < 0.05)

Mentions: DKK1 is a member of the dickopff family of secreted inhibitors of wnt signalling. DKK1 has been shown to block WNT2-induced cell growth in cultured fibroblasts and the WNT2-induced increase in uncomplexed beta-catenin Of note with respect to the pathogenesis of osteoporosis, was the finding that production of DKK1, which inhibits osteoblast differentiation, is associated with the presence of osteolytic bone lesions in patients with multiple myeloma. [35]. Figure 5 Panel A demonstrates temporally regulated induction of this mRNA by dexamethasone in primary human osteoblasts, with significant increases in expression detected 60 minutes post exposure, a trend that continued for 4 hours. These data lend further weight to the hypothesis that altered developmental networks drive the pathogenesis of steroid associated bone disease.

Hurson CJ, Butler JS, Keating DT, Murray DW, Sadlier DM, O'Byrne JM, Doran PP - BMC Musculoskelet Disord (2007)

Bottom Line: Functional characterization of the transcriptome identified developmental networks as being reactivated with 106 development associated genes found to be differentially regulated.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.

Affiliation: 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>

Abstract: 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.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.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.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.