by In addition, CKD increased total area and decreased cortical bone area fraction in the femora (Figure 5). R mice were killed at 28 weeks of age. CKD R, CKD V, chronic kidney disease mice treated with vehicle. CKD R, CKD+RAP-011.Figure S2. Effects of low-density lipoprotein receptor (high fat-fed mice (sham) compared with wild-type mice fed chow. Decreased properties include strength (yield and ultimate stress), deformability (strain), and resilience/toughness. NIHMS876802-supplement-Supplemental.pdf (161K) GUID:?9B607183-AFF7-4D3E-BD0B-241FA8D647D1 Abstract Dysregulation of skeletal remodeling is usually a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is usually 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 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 screening, and bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated high fat-fed mice. Sham-operated mice experienced low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast figures TSHR 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. high fat-fed mice harbors a low-turnover baseline osteodystrophy,7,9 and circulating Wnt inhibitors contribute to the effects of CKD.9 Because the ActRIIA ligand trap decreased circulating Dkk1, we focused on factors of the TGF- family produced by kidney disease that circulate and may perturb normal physiologic systemic processes. Here we demonstrate in our model that CKD stimulated bone remodeling and osteoclast activation is usually inhibited by the ActRIIA ligand trap. RESULTS To analyze the role of ActRIIA in the CKD-MBD, we utilized a ligand trap consisting of the murine extracellular domain name of ActRIIA fused to a murine IgG-Fc fragment. The experimental design of the ligand trap experiments in the high fatCfed mouse with ablative CKD is usually shown in Supplementary Physique S1. Baseline osteodystrophy harbored by sham-operated Idlr?/? mice We first characterized the state of the skeleton in the baseline control sham-operated mice because high-fat feeding26 and the high fat-fed mouse27,28 have been shown to produce a low-turnover osteodystrophy. The high fatmouse has insulin resistance that progresses to type 2 diabetes by 28 weeks of age.20,29 The mice (sham, the sham-operated group in these studies) harbor an osteodystrophy characterized histomorphometrically by relatively managed osteoclast numbers/surfaces compared with wild-type (WT) C57B6J mice (Determine 1). However, osteoblast figures/surfaces, bone formation rates, and osteoblast efficiency were significantly decreased in sham mice (Physique 2), and osteoid volume and surfaces were significantly decreased in sham mice as was the mineral apposition rate, but only a pattern toward decreased mineralization lag time was found (Physique 3). The decrease in osteoblast number in the sham mice is in agreement with our recent studies,9 but it is usually more pronounced than in Benserazide HCl (Serazide) our earlier studies.30,31 The basis for this phenotypic change in the sham mice is not known, but was associated with the change to blinded histomorphometry performed in Dr. Malluches laboratory. Although trabecular bone architecture was not significantly altered in the sham mice (Physique 4), total area and cortical bone area were decreased in the femoral midshaft (Physique 5). The effects of diabetes and the lipodystrophy around the mechanical properties of long bones Benserazide HCl (Serazide) assessed by 4-point bending of femora exhibited a profound decrease in fracture resistance. Structural differences (decreases in elastic, postyield and total displacement and work) were driven by tissue effects. In Benserazide HCl (Serazide) the tissue, there were significant decreases in strength (yield and ultimate stress) (Supplementary Physique S2) and strain that resulted in decreased resilience and toughness (Supplementary Physique S2) in the femora of sham mice compared with those of WT mice. Open in a separate window Physique 1 Effects of chronic kidney disease (CKD) and RAP-011 on osteoclasts and.
