Gene expression analysis in human osteoblasts exposed to dexamethasone identifies altered developmental pathways as putative drivers of osteoporosis

Abstract

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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 <it>in vitro </it>and microarray based transcriptome profiling completed.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Salvianolic acid B stimulates osteogenesis in dexamethasone-treated zebrafish larvae

“…Furthermore, studies confirm that GC elicits increased ROS production and subsequent OS in skeletal tissue [11][12][13] . These studies indicate that excessive GC may significantly contribute to bone loss, partially due to oxidative stress, and antioxidant treatment may counteract GC-induced osteopenia and osteoporosis.…”

Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

“…Dex has also recently been known to alter the gene expression in osteoblasts during specific developmental pathways [2], and to increase the expression of Dkk-1, a member of the Dickkopf family of secreted potent antagonists of Wnt signaling [4]. In addition, GCs increase c-myc, a cell cycle regulatory factor, in osteoblasts, which is modulated by GSK3b [33].…”

“…A percentage of the total cell number was represented. The values are expressed as mean ± SD intracellular signaling factor in the canonical Wnt/b-catenin pathway in osteoblasts [2,5], and has previously been found to induce apoptosis [9,10,21]. Furthermore the activation and regulation of GSK3b are dependent on phosphorylation [22].…”

“…Excess GC enhances direct responsiveness of osteoblasts and ultimately impairs bone formation, leading to changes in cell number and function [1]. GCs have been shown to have various actions in bone cells [2]; however the molecular mechanism of GCs involved in apoptosis of osteoblasts is poorly understood. The effect of GC on osteoblasts is related to the Wnt signal transduction.…”

Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts

“…Furthermore, during the course of the disease, leprosy patients often present with acute inflammatory episodes, known as reactions which are treated with long-term glucocorticoid (GC) therapy, which likely contributes to bone loss (Sugumaran 1998). Indeed, an excess of circulating GC has adverse effects on bone architecture, leading to a reduction in osteogenesis, osteoblast proliferation and production of specific proteins and interfering with a range of important signaling pathways (Cooper 2004, Canalis et al 2007, Hurson et al 2007). Nevertheless, the effects of GC use are almost indistinguishable from those of the underlying inflammatory diseases, the pathological hallmarks of which commonly include bone resorption (Hardy & Cooper 2009).…”