A Ligand Trap of the Activin Receptor Type IIA Inhibits Osteoclast Stimulation of Bone Remodeling in Diabetic Mice with Chronic Kidney Disease

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dc.contributor.authorSugatini, Toshifumi
dc.contributor.authorAgapova, Olga A.
dc.contributor.authorFang, Yifu
dc.contributor.authorBerman, Alycia G.
dc.contributor.authorWallace, Joseph M.
dc.contributor.authorMalluche, Hartmut H.
dc.contributor.authorFaugere, Marie-Claude
dc.contributor.authorSmith, William
dc.contributor.authorSung, Victoria
dc.contributor.authorHruska, Keith A.
dc.contributor.departmentDepartment of Biomedical Engineering, School of Engineering and Technologyen_US
dc.date.accessioned2017-08-02T16:23:01Z
dc.date.available2017-08-02T16:23:01Z
dc.date.issued2017-01
dc.description.abstractDysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr-/- high fat–fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr-/- high fat–fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A–enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin–A induced osteoclastogenesis.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationSugatani, T., Agapova, O. A., Fang, Y., Berman, A. G., Wallace, J. M., Malluche, H. H., ... & Hruska, K. A. (2017). Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease. Kidney International, 91(1), 86-95. http://dx.doi.org/10.1016/j.kint.2016.07.039en_US
dc.identifier.urihttps://hdl.handle.net/1805/13715
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.isversionof10.1016/j.kint.2016.07.039en_US
dc.relation.journalKidney Internationalen_US
dc.rightsPublisher Policyen_US
dc.sourceAuthoren_US
dc.subjectactivin Aen_US
dc.subjectchronic kidney diseaseen_US
dc.subjectactivin receptor type IIAen_US
dc.titleA Ligand Trap of the Activin Receptor Type IIA Inhibits Osteoclast Stimulation of Bone Remodeling in Diabetic Mice with Chronic Kidney Diseaseen_US
dc.typeArticleen_US
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