Modeling hepatic osteodystrophy in Abcb4 deficient mice

Hochrath, K; Ehnert, Sabrina; Ackert‐Bicknell, Cheryl; Lau, Yvonne; Schmid, Andrea; Krawczyk, Marcin; Hengstler, Jan G.; Dunn, Jordanne; Hiththetiya, K; Rathkolb, Birgit; Micklich, Kateryna; Hans, Wolfgang; Fuchs, Helmut; Gailus‐Durner, Valérie; Wolf, Eckhard; Angelis, Martin Hrabé de; Dooley, Steven; Paigen, Beverly; Wildemann, Britt; Lammert, Frank; Nüssler, Andreas K.

doi:10.1016/j.bone.2013.03.012

Cited by 24 publications

(22 citation statements)

References 47 publications

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“…These results are consistent with data obtained in the ATP-binding cassette transporter B4 knockout mouse ( Abcb4 −/− ), which is a well-established experimental model of hepatic disease. In addition to the compatible results regarding bone phenotypes obtained by micro-CT analysis, the present study also revealed similar results related to the serum levels of RANKL 21. In addition, our results showed that cirrhotic mice treated with pamidronate had significantly lower serum levels of RANKL.…”

Section: Discussionsupporting

confidence: 89%

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment

Spirlandeli¹,

Dick-de-Paula²,

Zamarioli³

et al. 2017

Clinics

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OBJECTIVES:The present study was designed to evaluate the bone phenotypes and mechanisms involved in bone disorders associated with hepatic osteodystrophy. Hepatocellular disease was induced by carbon tetrachloride (CCl4). In addition, the effects of disodium pamidronate on bone tissue were evaluated.METHODS:The study included 4 groups of 15 mice: a) C = mice subjected to vehicle injections; b) C+P = mice subjected to vehicle and pamidronate injections; c) CCl4+V = mice subjected to CCl4 and vehicle injections; and d) CCl4+P = mice subjected to CCl4 and pamidronate injections. CCl4 or vehicle was administered for 8 weeks, while pamidronate or vehicle was injected at the end of the fourth week. Bone histomorphometry and biomechanical analysis were performed in tibiae, while femora were used for micro-computed tomography and gene expression.RESULTS:CCl4 mice exhibited decreased bone volume/trabecular volume and trabecular numbers, as well as increased trabecular separation, as determined by bone histomorphometry and micro-computed tomography, but these changes were not detected in the group treated with pamidronate. CCl4 mice showed increased numbers of osteoclasts and resorption surface. High serum levels of receptor activator of nuclear factor-κB ligand and the increased expression of tartrate-resistant acid phosphatase in the bones of CCl4 mice supported the enhancement of bone resorption in these mice.CONCLUSION:Taken together, these results suggest that bone resorption is the main mechanism of bone loss in chronic hepatocellular disease in mice.

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Section: Discussionsupporting

confidence: 89%

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment

Spirlandeli¹,

Dick-de-Paula²,

Zamarioli³

et al. 2017

Clinics

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“…65 Hepatic osteodystrophycaused by calcium and vitamin D malabsorption leading to secondary hyperparathyroidism, rickets or osteomalaciais a significant extrahepatic expression of chronic cholestatic liver disease. 66 Besides, preclinical studies [67][68][69] in Abcb4 −/− mice indicate that vitamin D modulates biliary injury and fibrogenesis, and vitamin D deficiency seems to aggravate liver fibrosis in this animal model. Although the beneficial effects of vitamin D do not fully protect against liver fibrosis, the authors speculate that adequate supplementation may abate hepatic injury and confer antifibrotic effects.…”

Section: Medical Treatmentmentioning

confidence: 88%

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults

Stättermayer

Halilbasic

Wrba

et al. 2020

Journal of Hepatology

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The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotypephenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARa (peroxisome proliferator-activated receptor-a)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.

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“…Considering the classical actions of vitamin D, it is self-evident that decreased 25(OH)D levels constitute a major risk factor for developing systemic bone diseases such as hepatic osteodystrophy or diabetic osteopathy [ 17 , 27 , 60 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. Table 1 summarizes several studies regarding the effect of chronic diseases on 25(OH)D status and bone mineral density.…”

Section: Chronic Diseases As Risk Factor For Vitamin D Deficiency mentioning

confidence: 99%

“…Table 1 summarizes several studies regarding the effect of chronic diseases on 25(OH)D status and bone mineral density. In patients with chronic liver diseases, 25(OH)D deficiency is associated with decreased gene expression levels of CYP2R1, CYP27A1 and GC (vitamin D-binding protein) as well as increased DHCR7 (7-dehydrocholesterol reductase) gene expression levels in the liver which positively correlates with a decrease in bone mineral density [ 80 , 82 , 83 ]. Furthermore, activation of 25(OH)D to 1,25(OH)D in the kidney is hampered by diseases affecting liver function, e.g., progressed diabetes mellitus and chronic kidney diseases [ 84 ].…”

Section: Chronic Diseases As Risk Factor For Vitamin D Deficiency mentioning

confidence: 99%

Crucial Role of Vitamin D in the Musculoskeletal System

et al. 2016

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Vitamin D is well known to exert multiple functions in bone biology, autoimmune diseases, cell growth, inflammation or neuromuscular and other immune functions. It is a fat-soluble vitamin present in many foods. It can be endogenously produced by ultraviolet rays from sunlight when the skin is exposed to initiate vitamin D synthesis. However, since vitamin D is biologically inert when obtained from sun exposure or diet, it must first be activated in human beings before functioning. The kidney and the liver play here a crucial role by hydroxylation of vitamin D to 25-hydroxyvitamin D in the liver and to 1,25-dihydroxyvitamin D in the kidney. In the past decades, it has been proven that vitamin D deficiency is involved in many diseases. Due to vitamin D’s central role in the musculoskeletal system and consequently the strong negative impact on bone health in cases of vitamin D deficiency, our aim was to underline its importance in bone physiology by summarizing recent findings on the correlation of vitamin D status and rickets, osteomalacia, osteopenia, primary and secondary osteoporosis as well as sarcopenia and musculoskeletal pain. While these diseases all positively correlate with a vitamin D deficiency, there is a great controversy regarding the appropriate vitamin D supplementation as both positive and negative effects on bone mineral density, musculoskeletal pain and incidence of falls are reported.

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Modeling hepatic osteodystrophy in Abcb4 deficient mice

Cited by 24 publications

References 47 publications

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults

Crucial Role of Vitamin D in the Musculoskeletal System

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