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Integrative Bone Metabolomics-Lipidomics Strategy for Pathological Mechanism of Postmenopausal Osteoporosis Mouse Model.

ABSTRACT: Osteoporosis, characterized by bone mass reduction and increased fractures, has become a global health problem that seriously affects the health of people, especially postmenopausal women; however, the current pathogenesis of postmenopausal osteoporosis (PMOP) has not been thoroughly elucidated to date. In this study, bilateral ovariectomy was performed to establish an OVX mouse model of osteoporosis. UPLC-Q-TOF-MS-based lipidomics in combination with metabolomics were used to analyze the femur tissue of osteoporosis mice. We found that 11 polar metabolites and 93 lipid metabolites were significantly changed and were involved in amino acid metabolism, nucleotide metabolism and lipid metabolism. Among the lipids, fatty acyls, glycerolipids, glycerophospholipids, sphingolipids and sterols showed robust changes. These results revealed that several metabolic disorders caused by changes in the hormone levels in OVX, especially disordered lipid metabolism, are closely related to the imbalance between bone resorption and formation and may underlie the development of PMOP. The data generated via lipidomics and metabolomics presented in this study shows good applicability and wide coverage in the construction of the metabolic profile of bone tissue. Therefore, this approach may provide the pathway focusing and data support at the metabolite level for the in-depth mechanism of PMOP.

SUBMITTER: Zhao H

PROVIDER: S-EPMC6220250 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Integrative Bone Metabolomics-Lipidomics Strategy for Pathological Mechanism of Postmenopausal Osteoporosis Mouse Model.

Zhao Hongxia H Li Xiaoqun X Zhang Dianying D Chen Haiyan H Chao Yufan Y Wu Kaiwen K Dong Xin X Su Jiacan J

Scientific reports 20181107 1

Osteoporosis, characterized by bone mass reduction and increased fractures, has become a global health problem that seriously affects the health of people, especially postmenopausal women; however, the current pathogenesis of postmenopausal osteoporosis (PMOP) has not been thoroughly elucidated to date. In this study, bilateral ovariectomy was performed to establish an OVX mouse model of osteoporosis. UPLC-Q-TOF-MS-based lipidomics in combination with metabolomics were used to analyze the femur ...[more]

PMID: 30405156

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Project description:Postmenopausal osteoporosis (PMOP) has became 1 of most prevalent bone disorders with aging population. Liuwei Dihuang (LWDH) Pill, a classical kidney-tonifying prescription, is extensively used to treat PMOP in China. The aim of this study is to explore the pharmacological mechanisms of LWDH Pill against PMOP via network pharmacological strategy. The active ingredients of LWDH Pill were screened out from the Traditional Chinese Medicine System Pharmacology, Encyclopedia of Traditional Chinese Medicine and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine Databases, and their related target genes were fished in the UniProt database. Simultaneously, the GeneCards and DisGeNET databases were used to identify the target genes of PMOP. Through establishing a protein-protein interaction network, the overlapping genes between LWDH Pill and PMOP were identified to analyze their interactions and the hub target genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to predict the underlying biological processes (BP) and signaling pathways, respectively. A total of 64 active ingredients and 653 related target genes were identified in LWDH Pill, and 292 target genes were closely associated with PMOP. After matching the target genes between LWDH Pill and PMOP, 84 overlapping targets were obtained and considered as therapeutically relevant. Through construction of a protein-protein interaction network, we identified 20 hub target genes including IL6, INS, tumor necrosis factor, AKT1, vascular endothelial growth factor A, IGF1, TP53, IL1B, MMP9, JUN, LEP, CTNNB1, EGF, PTGS2, PPARG, CXCL8, IL10, CCL2, FOS and ESR1. Gene Ontology enrichment analysis suggested that LWDH Pill exerted anti-PMOP effects via regulating multiple BP including cell proliferation and apoptosis, oxidative stress, inflammation and angiogenesis. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed several pathways, such as PI3K-AKT pathway, mitogen-activated protein kinase pathway, hypoxia-inducible factors-1 pathway, tumor necrosis factor pathway, interleukin-17 (IL-17) pathway and FoxO pathway that might be involved in modulating the above BP. Through network pharmacological approach, we investigated the potential therapeutic mechanism of LWDH Pill against postmenopausal osteoporosis in a systemic perspective. These identified multi-targets and multi-pathways provide promising directions for further revealing more exact mechanisms.

Project description:Osteoporosis, a disease characterized by low bone mineral density (BMD), increases the risk for fractures. Conventional risk factors alone do not completely explain measured BMD or osteoporotic fracture risk. Metabolomics may provide additional information. We aim to identify BMD-associated metabolomic markers that are predictive of fracture risk. We assessed 209 plasma metabolites by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 1552 Framingham Offspring Study participants, and measured femoral neck (FN) and lumbar spine (LS) BMD 2 to 10 years later using dual-energy X-ray absorptiometry. We assessed osteoporotic fractures up to 27-year follow-up after metabolomic profiling. We identified 27 metabolites associated with FN-BMD or LS-BMD by LASSO regression with internal validation. Incorporating selected metabolites significantly improved the prediction and the classification of osteoporotic fracture risk beyond conventional risk factors (area under the curve [AUC] = 0.74 for the model with identified metabolites and risk factors versus AUC = 0.70 with risk factors alone, p = .001; net reclassification index = 0.07, p = .03). We replicated significant improvement in fracture prediction by incorporating selected metabolites in 634 participants from the Hong Kong Osteoporosis Study (HKOS). The glycine, serine, and threonine metabolism pathway (including four identified metabolites: creatine, dimethylglycine, glycine, and serine) was significantly enriched (false discovery rate [FDR] p value = .028). Furthermore, three causally related metabolites (glycine, phosphatidylcholine [PC], and triacylglycerol [TAG]) were negatively associated with FN-BMD, whereas PC and TAG were negatively associated with LS-BMD through Mendelian randomization analysis. In summary, metabolites associated with BMD are helpful in osteoporotic fracture risk prediction. Potential causal mechanisms explaining the three metabolites on BMD are worthy of further experimental validation. Our findings may provide novel insights into the pathogenesis of osteoporosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Project description:BackgroundObesity is associated with improved bone mass and microarchitecture in Caucasian individuals, but evidence in obese Asian individuals is lacking.ObjectiveTo analyze the areal bone mineral density (aBMD) and bone microarchitecture in normal-weight, overweight, and obese postmenopausal Chinese women.MethodsA total of 243 postmenopausal women from the Chinese Vertebral Osteoporosis Study (ChiVOS) were included and were divided into three groups (OB, obese group; OW, overweight group; NW, normal weight group) by BMI level. aBMD, trabecular bone score (TBS), and appendicular lean mass (ALM) were measured by dual-energy X-ray absorptiometry (DXA). Bone microarchitecture was measured by HR-pQCT at the distal radius and tibia. X-ray was performed to confirm vertebral fractures (VFs). Multiple linear regression was used to evaluate the correlations between bone parameters and ALM after adjusting for confounding variables.ResultsThe prevalence of VFs and clinical fractures were similar among the groups. Participants in the OB group showed a lower level of osteocalcin with comparable levels of other bone turnover markers (BTMs). The aBMD at several skeletal sites was higher in the OB group than in the NW group after adjusting for age (p<0.01 for all comparisons). At the radius, the OB group had a higher Ct.Ar, Tb.vBMD, Tb.BV/TV, Tb.N, Tb.Th, and Ct.Th than the NW group after adjusting for covariates (p<0.05 for all). Differences of a similar magnitude were found at the distal tibia. There was a trend of decreasing trend in Tb.Sp, Tb.1/N/SD, and Ct.Po among groups at both sites. However, the bone microarchitecture did not differ between participants with severe obesity (BMI≥35.0kg/m2) and those with 30.0≤BMI<35 kg/m2. Multiple linear regression revealed that the associations between ALM and most of the bone microarchitecture parameters at both sites were much stronger than the association between body weight and bone parameters.ConclusionWe have observed significant improvements in aBMD, bone geometry, and bone microarchitecture in obese postmenopausal Chinese women. Except for a lower level of osteocalcin in the OB group, no significant differences in BTMs were found among the groups. Compared with body weight, ALM may explain greater variance in the improvement of bone microarchitecture parameters.

Dataset Information

Integrative Bone Metabolomics-Lipidomics Strategy for Pathological Mechanism of Postmenopausal Osteoporosis Mouse Model.

Publications

Integrative Bone Metabolomics-Lipidomics Strategy for Pathological Mechanism of Postmenopausal Osteoporosis Mouse Model.

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