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

Metzger, Corinne E.; Swallow, Elizabeth A.; Stacy, Alexander J.; Allen, Matthew R.

doi:10.1371/journal.pone.0250438

Cited by 23 publications

(36 citation statements)

References 33 publications

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“…Bone resorption predominates in both high and low bone turnover disease and the resultant elevated serum Ca and Pi levels promote bone extra-skeletal (vascular) calcification ( Zheng et al 2016 ). In agreement with the results of this present study, others have also reported increased cortical porosity and compromised bone architecture in CKD rodent models although inconsistent effects on the cortical and trabecular compartments have been reported ( Miller et al 1998 , Ogirima et al 2006 , Jia et al 2013 , Metzger et al 2021 ). Although humans with CKD have been reported to have lower cortical BMD inconsistencies in trabecular and cortical BMD in CKD animal models also exist ( Lau et al 2013 , Nickolas et al 2013 ).…”

Section: Discussionsupporting

confidence: 93%

“…The current classification system and treatment strategy for ROD are based on changes in bone turnover, mineralization, and volume ( Kazama et al 2013 ). A decrease in bone mineral density (BMD) is particularly common in patients with late-stage disease ( Nickolas et al 2013 ), but animal models have shown a more varied response ( Lau et al 2013 , Bajwa et al 2018 , Metzger et al 2021 ). The other ROD-associated skeletal pathologies have been attributed to CKD-related metabolic and hormonal disturbances ( Zheng et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy

Hsu

Stephen

Dillon

et al. 2022

Journal of Endocrinology

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Patients with advanced chronic kidney disease (CKD) often present with skeletal abnormalities; a condition known as renal osteodystrophy (ROD). While Tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 are critical for bone mineralization, their role in the etiology of ROD is unclear. To address this, ROD was induced in both wild-type and Phospho1 knockout (P1KO) mice using dietary adenine supplementation. The mice presented with hyperphosphatemia, hyperparathyroidism, and elevated levels of FGF23 and bone turnover markers. In particular, we noted that in CKD mice, bone mineral density (BMD) was increased in cortical bone (p < 0.05) but decreased in trabecular bone (p < 0.05). These changes were accompanied by decreased TNAP (p < 0.01) and increased PHOSPHO1 (p < 0.001) expression in wild-type CKD bones. In P1KO CKD mice, the cortical BMD phenotype was rescued, suggesting that the increased cortical BMD of CKD mice was driven by increased PHOSPHO1 expression. Other structural parameters were also improved in P1KO CKD mice. We further investigated the driver of the mineralization defects, by studying the effects of FGF23, PTH, and phosphate administration on PHOSPHO1 and TNAP expression by primary murine osteoblasts. We found both PHOSPHO1 and TNAP expression to be down-regulated in response to phosphate and PTH. The in vitro data suggest that the TNAP reduction in CKD-MBD is driven by the hyperphosphatemia and/or hyperparathyroidism noted in these mice, while the higher PHOSPHO1 expression may be a compensatory mechanism. Increased PHOSPHO1 expression in ROD may contribute to the disordered skeletal mineralization characteristic of this progressive disorder.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy

Hsu

Stephen

Dillon

et al. 2022

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Bone resorption predominates in both high and low bone turnover disease and the resultant elevated serum Ca and Pi levels promote bone extra-skeletal (vascular) calcification (Zheng et al 2016). In agreement with the results of this present study, others have also reported increased cortical porosity and compromised bone architecture in CKD animal models although inconsistent effects on the cortical and trabecular compartments have been reported (Jia et al 2013; Metzger et al 2021; Miller et al 1998; Ogirima et al 2006). Although patients with CKD have been reported to have lower cortical BMD inconsistencies in trabecular and cortical BMD in CKD animal models also exist (Lau et al 2013b; Nickolas et al 2013).…”

Section: Discussionsupporting

confidence: 93%

“…The current classification system and treatment strategy for ROD are based on changes to bone turnover, mineralization, and volume (Kazama et al 2013). A decrease in bone mineral density (BMD) is particularly common in patients with late-stage disease (Nickolas et al 2013) but animal models have shown a more varied response (Bajwa et al 2018; Lau et al 2013a; Metzger et al 2021). The other ROD-associated skeletal pathologies, have been attributed to CKD-related metabolic and hormonal disturbances (Zheng et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy

Hsu

Stephen

Dillon

et al. 2021

Preprint

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Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder characterized by altered mineral and bone metabolism. The role of PHOSPHO1 and tissue-nonspecific alkaline phosphatase (TNAP) in controlling bone mineralization in CKD-MBD is unclear. We utilized the adenine-induced murine model of CKD-MBD in which mice present with hyperphosphatemia, hyperparathyroidism, and elevated FGF23 levels, and bone turnover markers. Micro-CT and histomorphometric analysis revealed microarchitectural changes to the trabecular and cortical bone of CKD mice. Furthermore, CKD cortical bone mineral density (BMD) was increased (p < 0.05) whereas CKD trabecular bone BMD was decreased (p < 0.05). These changes were accompanied by decreased Alpl mRNA expression (p < 0.001) and increased Phospho1 mRNA expression (p < 0.01) in CKD bones, which were confirmed at the protein level. Cortical bone BMD was unchanged in Phospho1 knockout (P1KO) CKD mice suggesting that the increased cortical BMD noted in CKD was driven by the increased PHOSPHO1 expression. Intriguingly, other structural parameters were improved in P1KO CKD mice. In an attempt to determine the causes of the mineralization defects noted in the CKD mice, we investigated the direct effects of FGF23, PTH, and phosphate (Pi) administration on PHOSPHO1 and TNAP expression by primary murine osteoblasts. PHOSPHO1 and TNAP expression were down-regulated in a concentration-dependent manner by Pi and PTH whereas the effects of FGF23 treatment, with or without klotho, were less marked. Osteoblast matrix mineralization was increased with Pi, decreased with PTH in a concentration-dependent manner and FGF23 had no effect. In summary, this pre-clinical model of CKD presented with hypomineralization of trabecular bone but hypermineralisation of cortical bone. Similarly, divergent expression levels of TNAP and PHOSPHO1 were noted in CKD. These novel observations implicate these key phosphatases in the etiology of CKD-MBD and may help explain the disordered skeletal mineralization characteristic of this progressive disorder.

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“…All treatment groups decreased levels of blood urea nitrogen (BUN), where CpG-ODN, p7249 (M13mp18), and Horse were significant relative to PBS+ treated mice albeit a nontoxic result, while CREAT levels remained unchanged (Figure 4C), likely indicating healthy kidney function. [46][47][48] Taken together, these multiple lines of toxicological evidence (weight, histopathology, biochemical panel, and lack of cytokine storm) indicate that Tri and Horse DO nanostructure treatments alone in vivo are nontoxic in response to repeat dosing at a high dose of 12.0 mg kg −1 .…”

Section: Toxicological Evaluation Of Tri and Horse Dna Origami Nanost...mentioning

confidence: 97%

DNA Origami Nanostructures Elicit Dose‐Dependent Immunogenicity and Are Nontoxic up to High Doses In Vivo

Lucas

Halley

Chowdury

et al. 2022

Small

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DNA origami (DO) nanotechnology enables the construction of precise nanostructures capable of functionalization with small molecule drugs, nucleic acids, and proteins, suggesting a promising platform for biomedical applications. Despite the potential for drug and vaccine delivery, the impact of DO vehicles on immunogenicity in vivo is not well understood. Here, two DO vehicles, a flat triangle and a nanorod, at varying concentrations are evaluated in vitro and with a repeated dosing regimen administered at a high dose in vivo to study early and late immunogenicity. The studies show normal CD11b+ myeloid cell populations preferentially internalize DO in vitro. DO structures distribute well systemically in vivo, elicit a modest pro‐inflammatory immune response that diminishes over time and are nontoxic as shown by weight, histopathology, lack of cytokine storm, and a complete biochemistry panel at the day 10 end point. The results take critical steps to characterize the biological response to DO and suggest that DO vehicles represent a promising platform for drug delivery and vaccine development where immunogenicity should be a key consideration.

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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

Cited by 23 publications

References 33 publications

Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy

Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy

Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy

DNA Origami Nanostructures Elicit Dose‐Dependent Immunogenicity and Are Nontoxic up to High Doses In Vivo

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