Session Title: Biology and Pathology of Bone and Joint
Session Type: Abstract Submissions (ACR)
Background/Purpose: Glucocorticoids are widely used as anti-inflammatory and immunosuppressive drug for the treatment of many inflammatory and auto-immune diseases. However, long-term and high-dose glucocorticoid treatment causes bone loss and can lead to secondary osteoporosis in both human and mice. The molecular mechanisms underlying the adverse effects of glucocorticoids on bone are not well understood. We have recently demonstrated that osteoblast-targeted disruption of glucocorticoid signalling attenuates glucocorticoid-induced bone loss in mice, indicating that the detrimental skeletal effects of glucocorticoids are predominantly mediated by osteoblasts. To elucidate the role of the osteoblast in glucocorticoid-induced bone loss, in the present study we determined the effects of glucocorticoids on the gene expression profile in bone cells.
Methods: Seven-week old male CD1 outbred mice were subcutaneously implanted with slow-release pellets containing either 1.5 mg corticosterone (CS) or placebo (PLC) over 28 days. Blood was obtained weekly and osteocalcin serum levels were measured by IRMA. RNA was isolated from tibia at endpoint (day 28) and Affymetrix Gene Array analysis (GeneSpring GX) was performed to assess changes in expression of genes associated with osteoblast differentiation and the regulation of bone remodelling. Genes considered to be regulated were at least 1.5-fold differentially expressed. Quantitative RT-PCR was employed to validate the gene array results on a selection of genes.
Results: By comparing gene expression profiles in tibial RNA from mice treated with CS or PLC, we found that CS specifically regulated 391 genes. To further investigate the genes targeted by corticosterone treatment we performed gene ontology analysis with the aid of heat maps. The expression of genes implicated in osteoblast differentiation and the regulation of bone remodelling was downregulated in mice treated with CS compared to the PLC-treated control group. More precisely, we observed a downregulation of the osteoblast markers Runx2, Colα1, osteocalcin and sclerostin in CS-treated mice compared to PLC. In addition, BMP4 and BMP7 followed the same pattern. Genes that were most profoundly downregulated in the array analysis were further validated by qRT-PCR. Consistent with mRNA levels, osteocalcin serum levels were suppressed to almost undetectable levels.
Conclusion: These results confirm that glucocorticoids primarily target genes involved in osteoblast differentiation and the regulation of bone remodelling. Gene expression profile analyses may point to the pathways involved in the negative effects of glucocorticoids on bone.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-negative-effects-of-glucocorticoids-on-bone-are-primarily-mediated-by-genes-involved-in-osteoblast-differentiation-and-bone-remodelling/