MicroRNA levels in bone and blood change during bisphosphonate and teriparatide therapy in an animal model of postmenopausal osteoporosis

Kocijan, R.; Weigl, M.; Skalicky, S.; Geiger, E.; Ferguson, J.; Leinfellner, G.; Heimel, P.; Pietschmann, P.; Grillari, J.; Redl, H.; Hackl, M.

doi:10.1101/591990

bioRxiv · 10.1101/591990

MicroRNA levels in bone and blood change during bisphosphonate and teriparatide therapy in an animal model of postmenopausal osteoporosis

Kocijan, R.·Weigl, M.·Skalicky, S.·Geiger, E.·Ferguson, J.·Leinfellner, G.·Heimel, P.·Pietschmann, P.·Grillari, J.·Redl, H.·Hackl, M.

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Abstract

MicroRNAs control the activity of a variety of genes that are pivotal to bone metabolism. Therefore, the clinical utility of miRNAs as biomarkers and drug targets for bone diseases certainly merits further investigation. This study describes the use of an animal model of postmenopausal osteoporosis to generate a comprehensive dataset on miRNA regulation in bone tissue and peripheral blood during bone loss and specifically anti-resorptive and osteo-anabolic treatment.\n\nForty-two Sprague-Dawley rats were randomized to SHAM surgery (n=10) or ovariectomy (OVX, n=32). Eight weeks after surgery, OVX animals were further randomized to anti-resorptive treatment with zoledronate (n=11), osteo-anabolic treatment with teriparatide (n=11), or vehicle treatment (n=10). After 12 weeks of treatment, bone and serum samples were used for microRNA analysis using next-generation sequencing (NGS), mRNA levels using RT-qPCR, and bone microarchitecture analysis using nanoCT.\n\nOvariectomy resulted in loss of trabecular bone, which was fully rescued using osteo-anabolic treatment, and partially rescued using anti-resorptive treatment. NGS revealed that both, anti-resorptive and anabolic treatment had a significant impact on miRNA levels in bone tissue and serum: out of 426 detected miRNAs, 46 miRNAs were regulated by teriparatide treatment an d 10 by zoledronate treatment (p-adj. < 0.1). Interestingly, teriparatide and zoledronate treatment were able to revert miRNA changes in tissue and serum of untreated OVX animals, such as the up-regulation of miR-203a-3p, a known osteo-inhibitory miRNA. We confirmed previously established mechanisms of miR-203a by analyzing its direct target Dlx5 in femoral head.\n\nOur data reveal a significant effect of ovariectomy-induced bone loss, as well as the two major types of anti-osteoporotic treatment on miRNA transcription in femoral head tissue. These changes are associated with altered activity of target genes relevant to bone formation, such as Dlx5. The observed effects of bone loss and treatment response on miRNA levels in bone are also reflected in the peripheral blood, suggesting the possibility of minimally-invasive monitoring of bone-derived miRNAs using liquid biopsies.\n\nHighlightsO_LImicroRNA expression in bone tissue is altered by osteo-anabolic and anti-resorptive therapy in OVX rats.\nC_LIO_LImicroRNA changes in untreated OVX rats are reverted by anti-osteoporotic therapy.\nC_LIO_LImiR-203a is up-regulated during bone loss and down-regulated following therapy.\nC_LIO_LIBone tissue and serum levels of miR-203a are highly correlated.\nC_LI

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Kocijan, R., Weigl, M., Skalicky, S., Geiger, E., Ferguson, J., Leinfellner, G., Heimel, P., Pietschmann, P., Grillari, J., Redl, H., Hackl, M.. 2019-03-29. MicroRNA levels in bone and blood change during bisphosphonate and teriparatide therapy in an animal model of postmenopausal osteoporosis. https://doi.org/10.1101/591990

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