New Molecules Modulating Bone Metabolism – New Perspectives in the Treatment of Osteoporosis

Žofková, I; Blahoś, J

doi:10.33549/physiolres.933720

Cited by 12 publications

(8 citation statements)

References 47 publications

(17 reference statements)

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“…Liu et al 39 showed that icariin could stimulate osteoblastic differentiation via the Wnt/β-catenin pathway. In addition, Zofkova et al 40 conducted a review and suggested that icariin could stimulate Wnt/β-catenin signaling and regulate the osteoblast activity.…”

Section: Discussionmentioning

confidence: 99%

Protection of Icariin Against Hydrogen Peroxide‐Induced MC3T3‐E1 Cell Oxidative Damage

Sun

Wang

2021

Orthopaedic Surgery

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Objective The aim of the present study was to evaluate the potential protective mechanism of icariin against oxidative damage caused by hydrogen peroxide in MC3T3‐E1 cells. Methods MC3T3‐E1 cells were treated with different concentrations of icariin to explore the optimal dose of icariin. MC3T3‐E1 cells were divided into groups treated with various concentrations of hydrogen peroxide (H2O2; 0, 0.1, 0.2, 0.5, 1, and 2 mM) for 24 h to induce oxidative damage and cell viability was assessed by Cell Counting Kit‐8 (CCK‐8) assay. Then, cells were divided into five groups: control, H2O2 (0.2 mM), icariin (0.1 μM) and H2O2 (0.2 mM), + icariin (0.1 μM). Cell viability was detected by CCK‐8 assay. In addition, the content of glutathione and superoxide dismutase and the activity level of malondialdehyde in these treatment groups were determined. Alkaline phosphatase (ALP) and alizarin red S (ARS) staining were also performed to measure the early and late osteogenesis, respectively. Protein expression of β‐catenin and cyclin D1 was measured by western blot assay. Then, we used an antagonist of Wnt/β‐catenin signaling pathway (DKK‐1) and western blot analysis to further explore potential mechanism. Results After 24 h of exposure to 0.2 mM H2O2, the viability of MC3T3‐E1 cells was significantly decreased compared to that of the control cells. We first found that icariin can promote cell proliferation of MC3T3‐E1 cells in a dose‐dependent manner, with the dosage 0.1 μM showing the best pro‐proliferative effect. Furthermore, icariin could promote the protein expression of OSX and RUNX2. The results showed that icariin can reverse the inhibitory osteogenic effects of MC3T3‐E1 caused by H2O2. In addition, icariin could increase the Wnt‐signaling related proteins. The results showed that MC3T3‐E1 cells in the H2O2 (0.2 mM) + icariin (0.1 μM) + Wnt‐signaling antagonist (DKK‐1) group had weaker ALP and ARS staining compared with that observed in the control and H2O2 (0.2 mM) + icariin (0.1 μM) groups. The ALP activity and calcium content were decreased in the 0.2 mM H2O2 + 0.1 μM icariin + DKK‐1 group compared to that observed in the 0.2 mM H2O2 + 0.1 μM icariin group. Conclusion The results showed that icariin can increase the viability of MC3T3‐E1 cells, reverse the oxidative stress induced by H2O2 and protect MC3T3‐E1 cells against H2O2‐induced inhibition of osteogenic differentiation, which may occur through the Wnt/β‐catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Protection of Icariin Against Hydrogen Peroxide‐Induced MC3T3‐E1 Cell Oxidative Damage

Sun

Wang

2021

Orthopaedic Surgery

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“…Because the OPG/RANKL/RANK signaling pathway, Wnt/b-catenin signaling pathway, and BMPs signaling pathway play an important role in regulating osteogenesis and osteoclast lineage function, as well as in regulating bone mass and bone remodeling, some protein molecules in these signaling pathways have become new targets for osteoporosis treatment. Targeted therapeutics for these targets have also entered clinical trials, but they are generally more expensive and have potential adverse effects [49][50][51][52][53][54]. This research shows that the active components of SWD can directly (purple circles in Figure 5) or indirectly (through pink circles to blue circles in Figure 5) regulate osteoporosis-related targets, thereby regulating "(hsa04010) MAPK signaling pathway", "(hsa04668) TNF signaling pathway", and "(hsa04064) NF-kappa B signaling pathway", as well as "(GO: 0071773) cellular response to BMP stimulus", "(GO: 0043410) positive regulation of MAPK cascade", "(GO: 0060070) canonical Wnt signaling pathway", and "(GO: 0046330) positive regulation of JNK cascade".…”

Section: Discussionmentioning

confidence: 99%

Systematic Pharmacological Methodology to Explore the Pharmacological Mechanism of Siwu Decoction for Osteoporosis

et al. 2019

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BackgroundOsteoporosis is an important health problem worldwide. Siwu decoction (SWD) and its modification have a good clinical effect on osteoporosis. However, the molecular mechanism of SWD on osteoporosis has not been thoroughly explained.Material/MethodsA systematic pharmacological methodology was utilized to predict the active compounds and potential targets of SWD, collect the genes of osteoporosis and the known targets of SWD, and analyze the osteoporosis and SWD’s network.ResultsFive networks were constructed and analyzed: (1) Osteoporosis genes’ protein–protein interaction (PPI) network; (2) Compound-compound target network of SWD; (3) SWD-osteoporosis PPI network; (4) Compound-known target network of SWD; and (5) SWD known target- osteoporosis PPI network. Several osteoporosis and treatment-related targets (eg.,. HSP90AB1, FGFR1, HRAS, GRB2, and PGF), clusters, biological processes, and signaling pathways (e.g., PI3K-Akt signaling pathway, insulin signaling pathway, MAPK signaling pathway and FoxO signaling pathway) were found.ConclusionsThe therapeutic effect of SWD on osteoporosis may be achieved by interfering with the biological processes and signaling pathways related to the development of osteoporosis.

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“…A large body of evidence has demonstrated increased risk of secondary osteoporosis associated with a chronic GC treatment. The findings from clinical and experimental studies suggest that GC-induced loss of skeletal mass arises from changes in the numbers of bone cells, altering a balance between osteoblast-dependent bone formation and osteoclast-mediated bone resorption ( 23 ). Disturbances in the bone tissue caused by GCs may also be closely related to deleterious changes in the vitamin D endocrine system.…”

Section: Discussionmentioning

confidence: 99%

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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New Molecules Modulating Bone Metabolism – New Perspectives in the Treatment of Osteoporosis

Cited by 12 publications

References 47 publications

Protection of Icariin Against Hydrogen Peroxide‐Induced MC3T3‐E1 Cell Oxidative Damage

Protection of Icariin Against Hydrogen Peroxide‐Induced MC3T3‐E1 Cell Oxidative Damage

Systematic Pharmacological Methodology to Explore the Pharmacological Mechanism of Siwu Decoction for Osteoporosis

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

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