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Browsing by Author "Metzger, Corinne E."
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Item A novel murine model of combined insulin-dependent diabetes and chronic kidney disease has greater skeletal detriments than either disease individually(Elsevier, 2022-12) Damrath, John G.; Metzger, Corinne E.; Allen, Matthew R.; Wallace , Joseph M.; Anatomy, Cell Biology and Physiology, School of MedicineDiabetes and chronic kidney disease (CKD) consistently rank among the top ten conditions in prevalence and mortality in the United States. Insulin-dependent diabetes (IDD) and CKD each increase the risk of skeletal fractures and fracture-related mortality. However, it remains unknown whether these conditions have interactive end-organ effects on the skeleton. We hypothesized that combining IDD and CKD in mice would cause structural and mechanical bone alterations that are more deleterious compared to the single disease states. Female C57BL6/J mice were divided into four groups: 1) N=12 Control (CTRL), 2) N=10 Streptozotocin-induced IDD (STZ), 3) N=10 Adenine diet-induced CKD (AD), and 4) N=9 Combination (STZ+AD). STZ administration resulted in significantly higher blood glucose, HbA1c (p<0.0001), and glucose intolerance (p<0.0001). AD resulted in higher blood urea nitrogen (p=0.0002) while AD, but not STZ+AD mice, had high serum parathyroid hormone (p<0.0001) and phosphorus (p=0.0005). STZ lowered bone turnover (p=0.001). Trabecular bone volume was lowered by STZ (p<0.0001) and increased by AD (p=0.003). Tissue mineral density was lowered by STZ (p<0.0001) and AD (p=0.02) in trabecular bone but only lowered by STZ in cortical bone (p=0.002). Cortical porosity of the proximal tibia was increased by AD, moment of inertia was lower in both disease groups, and most cortical properties were lower in all groups vs CTRL. Ultimate force, stiffness, toughness, and total displacement/strain were lowered by STZ and AD. Fracture toughness was lower by AD (p=0.003). Importantly, Cohen’s D indicated that STZ+AD most strongly lowered bone turnover and mechanical properties. Taken together, structural and material-level bone properties are altered by STZ and AD while their combination resulted in greater detriments, indicating that improving bone health in the combined disease state may require novel interventions.Item Adenine-induced chronic kidney disease induces a similar skeletal phenotype in male and female C57BL/6 mice with more severe deficits in cortical bone properties of male mice(PLOS, 2021-04-23) Metzger, Corinne E.; Swallow, Elizabeth A.; Stacy, Alexander J.; Allen, Matthew R.; Anatomy and Cell Biology, School of MedicineChronic kidney disease (CKD) causes bone loss, particularly in cortical bone, through formation of cortical pores which lead to skeletal fragility. Animal models of CKD have shown variability in the skeletal response to CKD between males and females suggesting sex may play a role in this variation. Our aim was to compare the impact of adenine-induced CKD on cortical parameters in skeletally mature male and female C57Bl/6 mice. After 10-weeks of adenine-induced CKD, both male and female adenine mice had high serum parathyroid hormone (PTH), high bone turnover, and cortical porosity compared to non-CKD controls. Both sexes had lower cortical thickness, but only male mice had lower cortical bone area. CKD imparted greater deficits in mechanical properties of male mice compared to female mice. These data demonstrate that both male and female mice develop high PTH/high bone turnover in response to adenine-induced CKD and that cortical bone phenotypes are slightly more severe in males, particularly in mechanical properties deficits.Item Age and sex effects on FGF23-mediated response to mild phosphate challenge(Elsevier, 2021) Tippen, Samantha P.; Noonan, Megan L.; Ni, Pu; Metzger, Corinne E.; Swallow, Elizabeth A.; Sacks, Spencer A.; Chen, Neal X.; Thompson, William R.; Prideaux, Matthew; Atkins, Gerald J.; Moe, Sharon M.; Allen, Matthew R.; White, Kenneth E.; Medical and Molecular Genetics, School of MedicineBackground: During aging, there is a normal and mild loss in kidney function that leads to abnormalities of the kidney-bone metabolic axis. In the setting of increased phosphorus intake, hyperphosphatemia can occur despite increased concentrations of the phosphaturic hormone FGF23. This is likely from decreased expression of the FGF23 co-receptor Klotho (KL) with age; however, the roles of age and sex in the homeostatic responses to mild phosphate challenges remain unclear. Methods: Male and female 16-week and 78-week mice were placed on either normal grain-based chow or casein (higher bioavailable phosphate) diets for 8 weeks. Gene expression, serum biochemistries, micro-computed tomography, and skeletal mechanics were used to assess the impact of mild phosphate challenge on multiple organ systems. Cell culture of differentiated osteoblast/osteocytes was used to test mechanisms driving key outcomes. Results: Aging female mice responded to phosphate challenge by significantly elevating serum intact FGF23 (iFGF23) versus control diet; males did not show this response. Male mice, regardless of age, exhibited higher kidney KL mRNA with similar phosphate levels across both sexes. However, males and females had similar blood phosphate, calcium, and creatinine levels irrespective of age, suggesting that female mice upregulated FGF23 to maintain blood phosphorus, and compromised renal function could not explain the increased serum iFGF23. The 17β-estradiol levels were not different between groups, and in vivo bone steroid receptor (estrogen receptor 1 [Esr1], estrogen receptor 2 [Esr2], androgen receptor [Ar]) expression was not different by age, sex, or diet. Trabecular bone volume was higher in males but decreased with both age and phosphate challenge in both sexes. Cortical porosity increased with age in males but not females. In vitro studies demonstrated that 17β-estradiol treatment upregulated FGF23 and Esr2 mRNAs in a dose-dependent manner. Conclusions: Our study demonstrates that aging female mice upregulate FGF23 to a greater degree during a mild phosphate challenge to maintain blood phosphorus versus young female and young/old male mice, potentially due to direct estradiol effects on osteocytes. Thus, the control of phosphate intake during aging could have modifiable outcomes for FGF23-related phenotypes.Item Cortical porosity occurs at varying degrees throughout the skeleton in rats with chronic kidney disease(Elsevier, 2022-08-17) Metzger, Corinne E.; Newman, Christopher L.; Tippen, Samantha P.; Golemme, Natalie T.; Chen, Neal X.; Moe, Sharon M.; Allen, Matthew R.; Anatomy, Cell Biology and Physiology, School of MedicineCortical porosity develops in chronic kidney disease (CKD) and increases with progressing disease. Cortical porosity is likely a prominent contributor to skeletal fragility/fracture. The degree to which cortical porosity occurs throughout the skeleton is not fully known. In this study, we assessed cortical bone porosity via micro-computed tomography at multiple skeletal sites in rats with progressive chronic kidney disease. We hypothesized that cortical porosity would occur in long bones throughout the body, but to a lesser degree in flat bones and irregular bones. Porosity was measured, using micro-CT, at 17 different skeletal sites in 6 male rats with CKD. Varying degrees of porosity were seen throughout the skeleton with higher porosity in flat and irregular bone (i.e. parietal bone, mandible) vs. long bones (p = 0.01) and in non-weightbearing bones vs. weightbearing bones (p = 0.01). Porosity was also higher in proximal sites vs. distal sites in long bones (p < 0.01 in all comparisons). There was large heterogeneity in porosity within skeletal sites across rats and within the same rat across skeletal sites. Correlations showed cortical porosity of the proximal tibia was positively associated with porosity at the other sites with the strongest correlation to the parietal bone and the weakest to the ulna. Overall, our data demonstrates varying and significant cortical bone porosity across the skeleton of animals with chronic kidney disease. These data point to careful selection of skeletal sites to assess porosity in pre-clinical studies and the potential for fractures at multiple skeletal sites in patients with CKD.Item Effect of Advanced Glycation End‐Products (AGE) Lowering Drug ALT‐711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD‐MBD(Wiley, 2019) Chen, Neal X.; Srinivasan, Shruthi; O'Neill, Kalisha; Nickolas, Thomas L.; Wallace, Joseph M.; Allen, Matthew R.; Metzger, Corinne E.; Creecy, Amy; Avin, Keith G.; Moe, Sharon M.; Medicine, School of MedicineChronic kidney disease–mineral bone disorder (CKD‐MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end‐products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD‐MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT‐711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT‐711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT‐711, with parallel decreases in left ventricular hypertrophy. ALT‐711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT‐711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD‐MBD with an AGE breaker ALT‐711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT‐711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD‐MBD. © 2019 American Society for Bone and Mineral Research.Item Effect of ovariectomy on the progression of chronic kidney disease-mineral bone disorder (CKD-MBD) in female Cy/+ rats(Springer Nature, 2019-05-28) Vorland, Colby J.; Lachcik, Pamela J.; Swallow, Elizabeth A.; Metzger, Corinne E.; Allen, Matthew R.; Chen, Neal X.; Moe, Sharon M.; Hill Gallant, Kathleen M.; Anatomy and Cell Biology, IU School of MedicineMale Cy/+ rats have shown a relatively consistent pattern of progressive kidney disease development that displays multiple key features of late stage chronic kidney disease-mineral bone disorder (CKD-MBD), specifically the development of cortical bone porosity. However, progression of disease in female Cy/+ rats, assessed in limited studies, is more heterogeneous and to date has failed to show development of the CKD-MBD phenotype, thus limiting their use as a practical model of progressive CKD-MBD. Animal and human studies suggest that estrogen may be protective against kidney disease in addition to its established protective effect on bone. Therefore, in this study, we aimed to determine the effect of ovariectomy (OVX) on the biochemical and skeletal manifestations of CKD-MBD in Cy/+ female rats. We hypothesized that OVX would accelerate development of the biochemical and skeletal features of CKD-MBD in female Cy/+ rats, similar to those seen in male Cy/+ rats. Female Cy/+ rats underwent OVX (n = 8) or Sham (n = 8) surgery at 15 weeks of age. Blood was collected every 5 weeks post-surgery until 35 weeks of age, when the rats underwent a 4-day metabolic balance, and the tibia and final blood were collected at the time of sacrifice. OVX produced the expected changes in trabecular and cortical parameters consistent with post-menopausal disease, and negative phosphorus balance compared with Sham. However, indicators of CKD-MBD were similar between OVX and Sham (similar kidney weight, plasma blood urea nitrogen, creatinine, creatinine clearance, phosphorus, calcium, parathyroid hormone, and no cortical porosity). Contrary to our hypothesis, OVX did not produce evidence of development of the CKD-MBD phenotype in female Cy/+ rats.Item The Effect of Single Versus Group μCT on the Detection of Trabecular and Cortical Disease Phenotypes in Mouse Bones(Wiley, 2021-03-05) Kohler, Rachel; Tastad, Carli A.; Stacy, Alexander J.; Swallow, Elizabeth A.; Metzger, Corinne E.; Allen, Matthew R.; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and TechnologyMicro‐computed tomography is a critical assessment tool for bone‐related preclinical research, especially in murine models. To expedite the scanning process, researchers often image multiple bones simultaneously; however, it is unknown if this impacts scan quality and alters the ability to detect differences between experimental groups. The purpose of this study was to assess the effect of multibone scanning on detecting disease‐induced changes in bone microarchitecture and mineral density by group scanning two murine models with known skeletal defects: the Col1a2 G610C/+ model of osteogenesis imperfecta and an adenine‐induced model of chronic kidney disease. Adult male femurs were scanned individually and in random groups of three and eight in a Bruker Skyscan 1172 and 1176, respectively, then assessed for standard trabecular and cortical bone measures. Although scanning methodology altered raw values, with trabecular microarchitecture values more affected than cortical properties, a disease phenotype was still detectable in both group and solo scans. However, tissue mineral density in both trabecular and cortical bone was significantly impacted by group versus solo scanning. Researchers may be able to use small groupings in a single μCT scan to expedite preclinical analyses when the overall bone phenotype is large to decrease costs and increase speed of discoveries; however the details of scanning (single or group) should always be reported.Item Effects of ferric citrate and intravenous iron sucrose on markers of mineral, bone, and iron homeostasis in a rat model of CKD-MBD(Oxford University Press, 2022) Biruete, Annabel; Metzger, Corinne E.; Chen, Neal X.; Swallow, Elizabeth A.; Vrabec, Curtis; Clinkenbeard, Erica L.; Stacy, Alexander J.; Srinivasan, Shruthi; O’Neill, Kalisha; Avin, Keith G.; Allen, Matthew R.; Moe, Sharon M.; Anatomy, Cell Biology and Physiology, School of MedicineBackground: Anemia and chronic kidney disease-mineral and bone disorder (CKD-MBD) are common and begin early in CKD. Limited studies have concurrently compared the effects of ferric citrate (FC) versus intravenous (IV) iron on CKD-MBD and iron homeostasis in moderate CKD. Methods: We tested the effects of 10 weeks of 2% FC versus IV iron sucrose in rats with moderate CKD (Cy/+ male rat) and untreated normal (NL) littermates. Outcomes included a comprehensive assessment of CKD-MBD, iron homeostasis and oxidative stress. Results: CKD rats had azotemia, elevated phosphorus, parathyroid hormone and fibroblast growth factor-23 (FGF23). Compared with untreated CKD rats, treatment with FC led to lower plasma phosphorus, intact FGF23 and a trend (P = 0.07) toward lower C-terminal FGF23. FC and IV iron equally reduced aorta and heart calcifications to levels similar to NL animals. Compared with NL animals, CKD animals had higher bone turnover, lower trabecular volume and no difference in mineralization; these were unaffected by either iron treatment. Rats treated with IV iron had cortical and bone mechanical properties similar to NL animals. FC increased the transferrin saturation rate compared with untreated CKD and NL rats. Neither iron treatment increased oxidative stress above that of untreated CKD. Conclusions: Oral FC improved phosphorus homeostasis, some iron-related parameters and the production and cleavage of FGF23. The intermittent effect of low-dose IV iron sucrose on cardiovascular calcification and bone should be further explored in moderate-advanced CKD.Item Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD(SpringerLink, 2020-04) Metzger, Corinne E.; Swallow, Elizabeth A.; Allen, Matthew R.; Anatomy and Cell Biology, School of MedicineChronic kidney disease (CKD) leads to significant bone loss primarily through the development of cortical porosity. In both patients and animal models of CKD, sustained elevations in serum parathyroid hormone (PTH) are associated with cortical porosity. In this study, we aimed to track the progression of cortical porosity and increased PTH utilizing the adenine-induced CKD model. Young female mice (8 weeks) were given 0.2% adenine to induce CKD. Tissues were collected from groups of adenine and age-matched control mice after 2, 6, and 10 weeks. Serum blood urea nitrogen was elevated at all time points in adenine mice, but serum PTH was only statistically elevated at the 10-week time point. Cortical porosity was sevenfold higher in 6-week adenine mice compared to age-matched controls and 14-fold higher in 10-week adenine mice vs. controls. Additionally, osteocyte receptor activator of nuclear factor κB ligand (RANKL) was elevated in adenine-fed mice, while annexin V, an early marker of cellular apoptosis, was mildly decreased in osteocytes in adenine-fed mice. Based on these results, we hypothesize high serum PTH signals to osteocytes prolonging their lifespan resulting in sustained RANKL which drives osteoclastic bone resorption in the cortex. In conclusion, our data show time-dependent elevations in serum PTH and cortical porosity in adenine-induced CKD mice and demonstrate changes in osteocyte RANKL and apoptosis which may contribute to the development of cortical pores.Item Inhibition of RANKL improves the skeletal phenotype of adenine-induced chronic kidney disease in mice(Oxford University Press, 2024-01-14) Metzger, Corinne E.; Kittaka, Mizuho; LaPlant, Alec N.; Ueki, Yasuyoshi; Allen, Matthew R.; Anatomy, Cell Biology and Physiology, School of MedicineSkeletal fragility and high fracture rates are common in CKD. A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that RANKL drives high bone resorption within cortical bone leading to the development of cortical porosity in CKD (study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype of CKD (study 2). In study 1, we assessed the skeletal properties of male and female Dmp1-cre RANKLfl/fl (cKO) and control genotype (Ranklfl/fl; Con) mice after 10 wk of adenine-induced CKD (AD; 0.2% dietary adenine). All AD mice regardless of sex or genotype had elevated blood urea nitrogen and high PTH. Con AD mice in both sexes had cortical porosity and lower cortical thickness as well as high osteoclast-covered trabecular surfaces and higher bone formation rate. cKO mice had preserved cortical bone microarchitecture despite high circulating PTH as well as no CKD-induced increases in osteoclasts. In study 2, male mice with established AD CKD were either given a single injection of an anti-RANKL antibody (5 mg/kg) 8 wk post-induction of CKD or subjected to 3×/wk dosing with risedronate (1.2 μg/kg) for 4 wk. Anti-RANKL treatment significantly reduced bone formation rate as well as osteoclast surfaces at both trabecular and cortical pore surfaces; risedronate treatment had little effect on these bone parameters. In conclusion, these studies demonstrate that bone-specific RANKL is critical for the development of high bone formation/high osteoclasts and cortical bone loss in CKD with high PTH. Additionally, systemic anti-RANKL ligand therapy in established CKD may help prevent the propagation of cortical bone loss via suppression of bone turnover.
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