Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease.
Dysregulation 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.
Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA.
Toshifumi
T
Sugatani
Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA.
Olga A
OA
Agapova
Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA.
Yifu
Y
Fang
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA.
Alycia G
AG
Berman
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA.
Joseph M
JM
Wallace
Division of Nephrology, Bone and Mineral Metabolism, Department of Medicine, University of Kentucky, Lexington, Kentucky, USA.
Hartmut H
HH
Malluche
Division of Nephrology, Bone and Mineral Metabolism, Department of Medicine, University of Kentucky, Lexington, Kentucky, USA.
Marie-Claude
MC
Faugere
Early Clinical Development, Celgene Corp., Basking Ridge, New Jersey, USA.
William
W
Smith
Translational Medicine, Celgene Corp., San Francisco, California, USA.
Victoria
V
Sung
Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA. Electronic address: Hruska_k@kids.wustl.edu.
Keith A
KA
Hruska
D028341:Activins / Q000378:metabolism*; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects*; D002478:Cells, Cultured; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000188:drug therapy* / Q000209:etiology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D054559:Hyperphosphatemia / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects*; D011973:Receptors, LDL / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D061205:Vascular Calcification / Q000209:etiology; D055114:X-Ray Microtomography
C000595663:ActRIIA-mIgG2aFc fusion protein; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; C422405:activin A; D028341:Activins
activin A; activin receptor type IIA; chronic kidney disease; renal osteodystrophy; signaling
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