IU Indianapolis ScholarWorks :: Browsing by Author "Swallow, Elizabeth A."

Browsing by Author "Swallow, Elizabeth A."

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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 Medicine
Chronic 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.
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 Medicine
Background: 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.
Assessing cortical bone porosity with MRI in an animal model of chronic kidney disease
(Elsevier, 2023) Newman, Christopher L.; Surowiec, Rachel K.; Swallow, Elizabeth A.; Metzger, Corinne E.; Kim, Jieun; Tomaschke, Andrew A.; Chen, Neal X.; Allen, Matthew R.; Wallace, Joseph M.; Moe, Sharon M.; Wu, Yu-Chien; Niziolek, Paul J.; Radiology and Imaging Sciences, School of Medicine
Chronic kidney disease (CKD) is characterized by secondary hyperparathyroidism and an increased risk of hip fractures predominantly related to cortical porosity. Unfortunately, bone mineral density measurements and high-resolution peripheral computed tomography (HR-pQCT) imaging have shortcomings that limit their utility in these patients. Ultrashort echo time magnetic resonance imaging (UTE-MRI) has the potential to overcome these limitations by providing an alternative assessment of cortical porosity. The goal of the current study was to determine if UTE-MRI could detect changes in porosity in an established rat model of CKD. Cy/+ rats (n = 11), an established animal model of CKD-MBD, and their normal littermates (n = 12) were imaged using microcomputed tomography (microCT) and UTE-MRI at 30 and 35 weeks of age (which approximates late-stage kidney disease in humans). Images were obtained at the distal tibia and the proximal femur. Cortical porosity was assessed using the percent porosity (Pore%) calculated from microCT imaging and the porosity index (PI) calculated from UTE-MRI. Correlations between Pore% and PI were also calculated. Cy/+ rats had higher Pore% than normal rats at both skeletal sites at 35 weeks (tibia = 7.13 % +/- 5.59 % vs. 0.51 % +/- 0.09 %, femur = 19.99 % +/- 7.72 % vs. 2.72 % +/- 0.32 %). They also had greater PI at the distal tibia at 30 weeks of age (0.47 +/- 0.06 vs. 0.40 +/- 0.08). However, Pore% and PI were only correlated in the proximal femur at 35 weeks of age (ρ = 0.929, Spearman). These microCT results are consistent with prior studies in this animal model utilizing microCT imaging. The UTE-MRI results were inconsistent, resulting in variable correlations with microCT imaging, which may be related to suboptimal bound and pore water discrimination at higher magnetic field strengths. Nevertheless, UTE-MRI may still provide an additional clinical tool to assess fracture risk without using ionizing radiation in CKD patients.
Blueberry Polyphenols do not Improve Bone Mineral Density or Mechanical Properties in Ovariectomized Rats
(Springer, 2022) Cladis, Dennis P.; Swallow, Elizabeth A.; Allen, Matthew R.; Hill Gallant, Kathleen M.; Weaver, Connie M.; Anatomy, Cell Biology and Physiology, School of Medicine
Osteoporosis-related bone fragility fractures are a major public health concern. Given the potential for adverse side effects of pharmacological treatment, many have sought alternative treatments, including dietary changes. Based on recent evidence that polyphenol-rich foods, like blueberries, increase calcium absorption and bone mineral density (BMD), we hypothesized that blueberry polyphenols would improve bone biomechanical properties. To test this, 5-month-old ovariectomized Sprague-Dawley rats (n = 10/gp) were orally gavaged for 90 days with either a purified extract of blueberry polyphenols (0-1000 mg total polyphenols/kg bw/day) or lyophilized blueberries (50 mg total polyphenols/kg bw/day). Upon completion of the dosing regimen, right femur, right tibia, and L1-L4 vertebrae were harvested and assessed for bone mineral density (BMD), with femurs being further analyzed for biomechanical properties via three-point bending. There were no differences in BMD at any of the sites analyzed. For bone mechanical properties, the only statistically significant difference was the high dose group having greater ultimate stress than the medium dose, although in the absence of differences in other measures of bone mechanical properties, we concluded that this result, while statistically significant, had little biological significance. Our results indicate that blueberry polyphenols had little impact on BMD or bone mechanical properties in an animal model of estrogen deficiency-induced bone loss.
Cortical porosity is elevated after a single dose of zoledronate in two rodent models of chronic kidney disease
(Elsevier, 2022-02-07) Swallow, Elizabeth A.; Metzger, Corrine E.; Chen, Neal X.; Wallace, Joseph M.; Tippen, Samantha P.; Kohler, Rachel; Moe, Sharon M.; Allen, Matthew R.; Anatomy, Cell Biology and Physiology, School of Medicine
Purpose: Patients with chronic kidney disease (CKD) have high risk of fracture in part due to cortical bone deterioration. The goal of this study was to assess the impact of two different bisphosphonates and dosing regimens on cortical microstructure (porosity, thickness, area) and bone mechanical properties in animal models of CKD. Methods: In experiment 1, Male Cy/+ (CKD) rats were treated with either a single dose or ten fractionated doses of zoledronate at 18 weeks of age. Fractionated animals received 1/10th of single dose given weekly for 10 weeks, with study endpoint at 28 weeks of age. In experiment 2, male C57Bl/6 J mice were given dietary adenine (0.2%) to induce CKD. Bisphosphonate treated groups were given either a single dose of zoledronate or weekly risedronate injections for 4 weeks. Cortical microstructure was assessed via μCT and mechanical parameters evaluated by monotonic bending tests. Results: Exp 1: CKD rats had higher blood urea nitrogen (BUN) and parathyroid hormone (PTH) compared to NL littermate controls. Single dose zoledronate had significantly higher cortical porosity in CKD S.Zol (2.29%) compared to NL control (0.04%) and untreated CKD (0.14%) (p = 0.004). Exp 2: All adenine groups had significantly higher BUN and PTH compared to control mice. Mice treated with single dose zoledronate (Ad + Zol) had the highest porosity (~6%), which was significantly higher compared to either Ad or Ad + Ris (~3%; p < 0.0001) and control mice had the lowest cortical porosity (0.35%). In both experiments, mechanics were minimally affected by any bisphosphonate dosing regimen. Conclusion: A single dose of zoledronate leads to higher cortical porosity compared to more frequent dosing of bisphosphonates (fractionated zoledronate or risedronate). Bisphosphonate treatment demonstrated limited effectiveness in preventing cortical bone microstructure deterioration with mechanical parameters remaining compromised due to CKD and/or secondary hyperparathyroidism irrespective of bisphosphonate treatment.
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 Medicine
Male 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.
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 Technology
Micro‐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.
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 Medicine
Background: 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.
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 Medicine
Chronic 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.
Erythropoietin and a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) lowers FGF23 in a model of chronic kidney disease (CKD)
(Wiley, 2020-03-31) Noonan, Megan L.; Clinkenbeard, Erica L.; Ni, Pu; Swallow, Elizabeth A.; Tippen, Samantha P.; Agoro, Rafiou; Allen, Matthew R.; White, Kenneth E.; Medical and Molecular Genetics, School of Medicine
Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor‐23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) FG‐4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 (“iFGF23”). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild‐type mice were fed an adenine‐containing diet to induce CKD, then injected with EPO or FG‐4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG‐4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein‐6 (Bmp‐6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF‐PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.

Browsing by Author "Swallow, Elizabeth A."

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