Moderate chronic kidney disease impairs bone quality in C57Bl/6J mice

Heveran, Chelsea M.; Ortega, Alicia M.; Cureton, Andrew; Clark, Ryan; Livingston, Eric W.; Bateman, Ted A.; Levi, Moshe; King, Karen B.; Ferguson, Virginia L.

doi:10.1016/j.bone.2016.02.006

Cited by 21 publications

(39 citation statements)

References 42 publications

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“…Yield load was even significantly increased in the 5/6 Nx-3 group compared to the Sham-3 group. Several studies assessed the bone quality in animals with subtotal nephrectomy using biomechanical tests (Jokihaara et al, 2006 ; Iwamoto et al, 2012 ; Heveran et al, 2016 ); the findings of these studies were in agreement with our results. The unexpected biomechanical data suggest that the early adaptive response related to growth in the very young, rapidly growing rats could provide protection from the deleterious effects of the moderate CKD on the cortical bone strength.…”

Section: Discussionsupporting

confidence: 91%

“…The animal model induced by subtotal nephrectomy (5/6 Nx) mimics the progressive renal disease in humans and is used to assess the pathophysiological aspects and the bone structural and biomechanical changes in moderate CKD (Moscovici et al, 1996 ; Heveran et al, 2016 ). We used growing rats to better understand the bone pathophysiology at two different time points of disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…The level of creatinine was significantly higher in older compared to younger animals with CKD, which may indicate progression of the disease. Changes in above parameters may mimic mild or moderate CKD (Jokihaara et al, 2006 ; Moe et al, 2009 ; Heveran et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moderate CKD impairs bone microarchitecture and decreases bone material quality in male C57Bl/6J mice after 5/6 nephrectomy (Heveran et al, 2016 ). Patients with moderate CKD have a two-fold increase in fracture prevalence compared with age-matched controls (Naylor et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

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Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

et al. 2017

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The diagnosis and treatment of bone disorders in patients with chronic kidney disease (CKD) represent a clinical challenge. CKD leads to mineral and bone complications starting early in the course of renal failure. Recently, we have observed the positive relationship between intensified central kynurenine turnover and bone strength in rats with subtotal 5/6 nephrectomy (5/6 Nx)-induced CKD. The aim of the present study was to determine the association between peripheral kynurenine pathway metabolites and bone strength in rats with 5/6 Nx-induced CKD. The animals were sacrificed 1 and 3 months after 5/6 Nx or sham operation. Nephrectomized rats presented higher concentrations of serum creatinine, urea nitrogen, and parathyroid hormone both 1 and 3 months after nephrectomy. These animals revealed higher concentrations of kynurenine and 3-hydroxykynurenine in the serum and higher gene expression of aryl hydrocarbon receptor (AhR) as a physiological receptor for kynurenine and AhR-dependent cytochrome in the bone tissue. Furthermore, nephrectomy significantly increased the number of osteoclasts in the bone without affecting their resorptive activity measured in serum. These changes were particularly evident in rats 1 month after 5/6 Nx. The main bone biomechanical parameters of the tibia were unchanged between nephrectomized and sham-operated rats but were significantly increased in older compared to younger animals. A similar trend was observed for geometrical parameters measured with calipers, bone mineral density based on Archimedes' method and image of bone microarchitecture obtained from micro-computed tomography analyses of tibial cortical bone. In nephrectomized animals, peripheral kynurenine levels correlated negatively with the main parameters of bone biomechanics, bone geometry, and bone mineral density values. In conclusion, our data suggest that CKD-induced elevated levels of peripheral kynurenine cause pathological changes in bone structure via AhR pathway. This finding opens new opportunities for the treatment/prevention of osteoporosis in CKD.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

et al. 2017

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“…Previous studies have employed an 5/6 nephrectomy (5/6 Nx) animal model to evaluate CKD-MBD (10,11). At 16 weeks following 5/6 Nx, diminished bone microarchitecture was observed in the tibial trabecular bone of cluster of differentiation 1 mice (11), which is a well-established mouse model to produce moderate CKD with high-turnover bone injury.…”

Section: Introductionmentioning

confidence: 99%

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

et al. 2018

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Abstract. Dietary calcium (Ca) supplementation has beneficial effects on bone health. However, it is not clear whether a high calcium diet (HCD) following 5/6 nephrectomy (5/6 Nx) is beneficial to bone health. The aim of the present study was to examine the effects of an HCD on bone metabolism using a chronic kidney disease (CKD) mouse model. Male C57BL/6J mice were divided into three groups: Sham group, 5/6 Nx group and 5/6 Nx + HCD group. Mice were sacrificed 12 weeks post-surgery. Calcium (Ca) and creatinine (Cr) were measured using standard colorimetric methods and picric acid methods, respectively. Bone metabolism-associated markers, FGF-23, PTH, ALP-b and TRAP-5b were measured using ELISA kits. Lumbar vertebrae histomorphological analysis was performed using hematoxylin and eosin staining. The expression of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) mRNA was detected using reverse transcription-quantitative polymerase chain reaction. Impaired renal function and histopathological damage was indicated in 5/6 Nx mice. However, HCD had no significant effects on these changes in 5/6 Nx mice. Notably, mineral metabolism disorder and histopathological damage to lumbar vertebrae were markedly improved in HCD-treated 5/6 Nx mice. Compared with 5/6 Nx mice, HCD supplementation significantly elevated the ratio of OPG/RANKL and inhibited RANKL mRNA expression in lumbar vertebrae. To conclude, the present findings indicated that increased Ca intake is effective in increasing bone mineral content of the lumbar vertebrae in 5/6 Nx mice. These results may provide a basis for the clinical use of dietary Ca supplementation as a therapeutic approach to treat CKD-induced disturbance of mineral metabolism and bone loss.

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Cinacalcet Improves Bone Parameters Through Regulation of Osteoclast Endoplasmic Reticulum Stress, Autophagy, and Apoptotic Pathways in Chronic Kidney Disease–Mineral and Bone Disorder

Chiu

Hou

et al. 2020

Journal of Bone and Mineral Research

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The possible mechanisms underlying the quantitative and qualitative effects of cinacalcet on bone were explored in a chronic kidney disease–mineral and bone disorder (CKD‐MBD) mouse model in relation to the influence of the interactions among the osteoclast (OC) endoplasmic reticulum (ER) stress, autophagy and apoptosis pathways on OC differentiation. Body weight and biochemical parameters improved significantly in the CKD + cinacalcet groups compared to the CKD group. Micro–computed tomography (μCT) revealed both cortical and trabecular parameters deteriorated significantly in the CKD group and were reversed by cinacalcet in a dose‐dependent manner. Nanoindentation analysis of bone quality proved that both cortical hardness and elastic modulus improved significantly with high dose cinacalcet treatment. In vitro studies revealed that cinacalcet inhibited receptor activator of NF‐κB ligand (RANKL)/receptor activator of NF‐κB (RANK)–induced OC differentiation in a concentration‐dependent manner through a close interaction between activation of caspase‐related apoptosis, reversal of OC autophagy through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and adenosine monophosphate–activated protein kinase (AMPK) pathways, and attenuation of the OC ER stress/CREBH/NFATc1 signaling pathway. Cinacalcet improves both bone quantity and bone quality in CKD mouse model and inhibits OC differentiation through regulation of the interactions among the apoptosis, ER stress, and autophagy pathways within OCs. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Moderate chronic kidney disease impairs bone quality in C57Bl/6J mice

Cited by 21 publications

References 42 publications

Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

Cinacalcet Improves Bone Parameters Through Regulation of Osteoclast Endoplasmic Reticulum Stress, Autophagy, and Apoptotic Pathways in Chronic Kidney Disease–Mineral and Bone Disorder

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