Молекулярно-Клітинні Механізми Захисної Дії Вітаміну D3 При Експериментальному Преднізолон-Індукованому Остеопорозі

Shymanskyi, Ihor; Lisakovska, Olha; Veliky, M. M.

doi:10.22141/2224-1507.7.3.2017.116863

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…As for osteoclastogenesis, available scientific data indicate that both the decrease and increase in this process can account for the bone loss, provided that there is a concomitant decline in the formation and functional ability of osteoblasts ( 33 , 34 ). Several recent studies which largely correspond to experimental design of the present investigation has demonstrated that chronic exposure of high GC doses had inhibiting effects both on bone formation and bone resorption ( 35 , 36 ). The discrepancy between prednisolone-induced osteoclastogenic profiles of cytokines, the increase in the number of circulating RANK-positive cells, and the low bone turnover can be explained by suppressed recruitment of OCPs from the BM to the bones.…”

Section: Discussionsupporting

confidence: 53%

Vitamin D3 Modulates Impaired Crosstalk Between RANK and Glucocorticoid Receptor Signaling in Bone Marrow Cells After Chronic Prednisolone Administration

et al. 2018

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The effectiveness of vitamin D3 (cholecalciferol) in counteracting the side effects of glucocorticoid (GC) therapy has been demonstrated previously. Abnormalities in systemic hormonal and local (cytokine) regulation of bone marrow (BM) cells may underlie GC-induced imbalance between osteosynthesis and bone resorption. The cytokine system receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) is considered as an integrating link in the NF-κB-mediated interaction of various cells involved in maintaining osteoblastic-osteoclastic balance, which makes it a pharmacological target for regulation and correction of the bone remodeling process. We studied GC-induced impairments of the RANKL/RANK/OPG axis in BM cells depending on vitamin D bioavailability and whether these changes were mediated by glucocorticoid (GR) and/or vitamin D (VDR) receptors. Female Wistar rats administered with prednisolone (5 mg/kg b.w., 30 days) showed a decrease in the GR protein level and the number of GR-positive BM cells. GC caused a marked elevation of RANKL and RANK levels in BM, while OPG decreased. Flow cytometry data indicated GC-elicited increase in the number of circulating RANK-positive osteoclast precursors (OCPs) in BM, peripheral blood, and spleen. In full accordance with the data that the interaction of RANKL-RANK leads to transcriptional activation of NF-κB and subsequent differentiation of osteoclasts, we found an increase in the level of phosphorylated p65 subunit of NF-κB with a simultaneous decrease in the NF-κB inhibitor (IκB) level. These changes were accompanied by vitamin D insufficiency and downregulated expression of CYP27B1 and VDR, which are responsible for synthesis and hormonal signaling of 1,25(OH)2D. Notably, we observed VDR and RANK co-localization in OCPs. Cholecalciferol co-administration (1,000 IU/kg b.w., 30 days) with prednisolone resulted in elevated GR synthesis in BM. Cholecalciferol prevented prednisolone-elicited disturbances of the RANKL/RANK/OPG, which correlated with improved bioavailability and vitamin D signaling through VDR. This caused the lowering of phosphoNF-κB p65 level and inhibiting NF-κB translocation to the nucleus that could reduce the circulating OCPs pool in BM, peripheral blood, and spleen. Our findings suggest that prednisolone-induced abnormalities in GR and RANKL/RANK/OPG signaling pathways are associated with the impairments of vitamin D auto/paracrine system in BM cells and can be ameliorated by cholecalciferol supplementation.

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Section: Discussionsupporting

confidence: 53%

Vitamin D3 Modulates Impaired Crosstalk Between RANK and Glucocorticoid Receptor Signaling in Bone Marrow Cells After Chronic Prednisolone Administration

et al. 2018

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“…We established that prednisolone administration caused a decrease in Vdr mRNA level by 1.37-fold that may contribute to antiosteoblastic effects of GC ( Figure 2(a) ). This is consistent with the previous results indicating lower VDR protein level in bone tissue after prednisolone load [ 23 ]. Reduced VDR level in bone tissue may be attributable to a possible decrease in cell responsiveness to vitamin D action and, as a result, impaired local auto-/paracrine regulation of cell function by vitamin D. At the same time, a 1.71-fold increase in the expression of Cyp27b1 mRNA in bone tissue was shown ( Figure 2(b) ), which suggests a compensatory response to lower levels of the components of the vitamin D auto-/paracrine system, 25(OH)D and VDR.…”

Section: Resultssupporting

confidence: 94%

“…Immunofluorescence staining of rat femur sections with anti-RANK-antibody showed the lowering of RANK level in prednisolone-administered rats ( Figure 4 ). These data are in agreement with our previous results that revealed a decrease in the protein level of RANK in bone tissue [ 23 ]. Moreover, the study on BALB/c male mice demonstrated that the number of osteoclasts in the areas of bone destruction was significantly decreased in the GC-treated animals compared with the control group [ 30 ].…”

Section: Resultssupporting

confidence: 94%

Vitamin D Auto-/Paracrine System Is Involved in Modulation of Glucocorticoid-Induced Changes in Angiogenesis/Bone Remodeling Coupling

Lisakovska

Shymanskyi

Labudzynskyi

et al. 2020

International Journal of Endocrinology

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Osteoporosis is a devastating side effect of chronic glucocorticoid (GC) treatment. Despite the crucial role of vitamin D (VD) in bone homeostasis, the precise molecular mechanisms of its action on GC-induced disturbances of bone remodeling remain undefined. The study was performed to elucidate the relation of VD status to GC-induced changes of the angiogenesis/osteogenesis/bone resorption coupling in bone tissue. Female Wistar rats received prednisolone (5 mg/kg of b.w.) with or without VD3 (1000 IU/kg of b.w., for 30 days). Biomechanical parameters of rat femurs were assessed by the three-point bending test. The levels of calcium, inorganic phosphate, activity of total alkaline phosphatase (ALP), and its isoenzymes were determined spectrophotometrically. Vascular endothelial growth factor-A (VEGF-A) and caspase-3 protein levels were detected by western blotting. Vdr and Cyp27b1 mRNAs were measured by qRT-PCR. Receptor activator of nuclear factor κB (RANK) expression in bone sections was visualized immunohistochemically. Serum 25(OH)D was assayed by ELISA. GC administration led to a decrease in maximal load (by 1.2-fold) and stiffness and toughness (by 1.3-fold), which was accompanied by a 3-fold reduction of 25(OH)D level, an elevation of the ALP bone isoenzyme activity in serum, hypocalcaemia, and hypophosphatemia. Along with prednisolone-induced VD deficiency, an impaired synthesis of Vdr (−30%) and Cyp27b1 (+71%) mRNA was observed, reflecting deregulation of bone tissue VD-auto-/paracrine system. GC caused an increase in caspase-3 content, suppressed the synthesis of the osteoclastic marker RANK, and altered angiogenesis/osteogenesis coupling by significantly reducing the level of VEGF-A.VD3 treatment restored serum 25(OH)D content and the expression of key components of the VD-auto-/paracrine system. VD3 supplementation diminished cell apoptosis and strongly improved angiogenesis/osteogenesis coupling as well as mineral metabolism and biomechanical parameters of femurs in GC-administered rats. Thus, VD3 can have a beneficial effect on the correction of GC-induced pathological changes in bone remodeling.

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The state of the liver, reproductive and musculoskeletal systems in female rats with pro-longed exposure to α-cypermethrin

Makarenko,

Sidletskiy,

Khodakov

2024

Regul. Mech. Biosyst.

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Pyrethroid insecticides are currently a widely used class of pesticides. It is therefore important to determine the mechanism of disorders in some mammalian systems due to prolonged exposure to these pesticides and to justify means to prevent poisoning complications. The study was conducted on 30 female rats aged 3 months for 120 days. Intoxication was modeled using α-cypermethrin at a dose of 10 mg/kg. The prevention of intoxication complications was carried out with an adaptogenic complex consisting of the flavonoid quercetin, vitamins C and D3, and minerals (Ca, Mn, Zn, Cu, Se, Mg) at a dose of 500 mg/kg. Assessment of intoxication and preventive efficacy of the adaptogen was performed by determining the duration of the estrous cycle, ovarian organ index, degree of atrophy of the alveolar process in the jaws, as well as density, content of mineral and organic components in the bones. Hepatotoxicity markers were determined in the blood serum, osteoresorption markers in the alveolar bone homogenate, inflammation indicators in the liver, and antioxidant system status in all tissues. Prolonged exposure to α-cypermethrin was associated with a prolongation of the estrous cycle due to a reduction in the diestrus stage and a decrease in the ovarian organ index along with a significant increase in blood estradiol levels. In intoxicated animals, the degree of atrophy of the alveolar process increased and the density of femurs and vertebrae decreased due to a decrease in the weight fraction of the mineral component in the bones. In the bone tissue of the alveolar process, an increase in the activity of elastase and markers of oxidative stress (an increase in the content of malondialdehyde and a decrease in catalase activity), as well as a compensatory increase in the alkaline phosphatase activity were found. In the rat liver, an increase in the acid phosphatase activity and the inhibition of antioxidant defense were observed. An increase in the elastase activity and a decrease in the catalase activity with an increase in the malondialdehyde content were found in the serum of the animals. The use of an adaptogen under conditions of α-cypermethrin intoxication contributed to the normalization of the estrous cycle, ovarian organ index and blood estradiol levels. In the tissue of the femur and vertebrae of rats, the treatment by the prophylactic complex led to an increase in bone density due to an increase in the content of the mineral component, and a decrease in the degree of atrophy of the jaws, in the tissue of which the activation of the enzymatic link of antioxidant defense and a decrease in the activity of destructive elastase too were found. The developed adaptogen prevented the development of oxidative stress and inflammation in the blood serum and liver in the animals. The results of the research indicate a negative effect of α-cypermethrin on the sexual function in female rats, on the state of bone tissue along with the hepatotoxic effect of the pesticide. The proposed agent for the prevention of α-cypermethrin intoxication effectively prevented endocrine disruption in the ovaries, bone destruction and inflammation in the liver.

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Молекулярно-Клітинні Механізми Захисної Дії Вітаміну D3 При Експериментальному Преднізолон-Індукованому Остеопорозі

Cited by 3 publications

References 20 publications

Vitamin D3 Modulates Impaired Crosstalk Between RANK and Glucocorticoid Receptor Signaling in Bone Marrow Cells After Chronic Prednisolone Administration

Vitamin D3 Modulates Impaired Crosstalk Between RANK and Glucocorticoid Receptor Signaling in Bone Marrow Cells After Chronic Prednisolone Administration

Vitamin D Auto-/Paracrine System Is Involved in Modulation of Glucocorticoid-Induced Changes in Angiogenesis/Bone Remodeling Coupling

The state of the liver, reproductive and musculoskeletal systems in female rats with pro-longed exposure to α-cypermethrin

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