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Global urinary metabolic profiling of the osteonecrosis of the femoral head based on UPLC–QTOF/MS

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Abstract

Introduction

Osteonecrosis of the femoral head (ONFH), one of the widespread orthopedic diseases with a decrease in bloodstream to the femoral head, is frequently accompanied by cellular death, trabecula fracture, and collapse of the articular surface. The exactly pathological mechanism of ONFH remains to explore and further identify.

Objectives

The aim was to identify the global urinary metabolic profiling of ONFH and to detect biomarkers of ONFH.

Methods

Urine samples were collected from 26 ONFH patients and 26 healthy people. Ultra-performance liquid chromatography–quadrupole time of flight tandem mass spectrometry (UPLC-QTOF/MS) in combination with multivariate statistical analysis was developed and performed to identify the global urinary metabolic profiling of ONFH.

Results

The urinary metabolic profiling of ONFH group was significantly separated from the control group by multivariate statistical analysis. 33 distinctly differential metabolites were detected between the ONFH patients and healthy people. Sulfate, urea, Deoxycholic acid and PE(14:0/14:1(9Z)) were screened as the potential biomarkers of ONFH. In addition, the up/down-regulation of sulfur metabolism, cysteine and methionine metabolism, glycerophospholipid metabolism, and histidine metabolism were clearly be associated with the ONFH pathogenic progress.

Conclusion

Our results suggested that metabolomics could serve as a promising approach for identifying the diagnostic biomarkers and elucidating the pathological mechanism of ONFH.

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References

  • Aranibar, N., Vassallo, J. D., Rathmacher, J., et al. (2011). Identification of 1- and 3-methylhistidine as biomarkers of skeletal muscle toxicity by nuclear magnetic resonance-based metabolic profiling. Analytical Biochemistry, 410(1), 84–91.

    Article  CAS  PubMed  Google Scholar 

  • Back, S. H., Adapala, N. S., Barbe, M. F., Carpino, N. C., Tsygankov, A. Y., & Sanjay, A. (2006). A novel role of l-serine (l-Ser) for the expression of nuclear factor of activated T cells (NFAT)2 in receptor activator of nuclear factor kB ligand (RANKL)-induced osteoclastogenesis in vitro. Journal of Bone and Mineral Metabolism, 24(5), 373–379.

    Article  CAS  Google Scholar 

  • Back, S. H., Adapala, N. S., Barbe, M. F., Carpino, N. C., Tsygankov, A. Y., & Sanjay, A. (2013). TULA-2, a novel histidine phosphatase regulates bone remodeling by modulating osteoclast function. Cellular and Molecular Life Sciences, 70(7), 1269–1284.

    Article  CAS  PubMed  Google Scholar 

  • Bahtiar, A., Matsumoto, T., Nakamura, T., et al. (2009). Identification of a novel l-serine analog that suppresses osteoclastogenesis in vitro and bone turnover in vivo. Journal of Biological Chemistry, 284(49), 34157–34166.

    Article  CAS  PubMed  Google Scholar 

  • Bijlsma, S., Bobeldijk, I., Verheij, E. R., et al. (2006). Large-scale human metabolomics studies: A strategy for data (pre-) processing and validation. Analytical Chemistry, 78, 567–574.

    Article  CAS  PubMed  Google Scholar 

  • Blachier, F., Mariotti, F., Huneau, J. F., & Tome´, D. (2007). Effects of amino acid-derived luminal metabolites on the colonic epithelium and physiopathological consequences. Amino Acids, 33, 547–562.

    Article  CAS  PubMed  Google Scholar 

  • Blouin, S., Thaler, H. W., Korninger, C., et al. (2009). Bone matrix quality and plasma homocysteine levels. Bone, 44, 959–964.

    Article  CAS  PubMed  Google Scholar 

  • Calder, J. D., Buttery, L., Revell, P. A., Pearse, M., & Polak, J. M. (2004). Apoptosis—A significant cause of bone cell death in osteonecrosis of the femoral head. Journal of Bone and Joint Surgery British, 86(8), 1209–1213.

    Article  CAS  Google Scholar 

  • Chierico, L., Joseph, A. S., Lewis, A. L., & Battaglia, G. (2014). Live cell imaging of membrane/cytoskeleton interactions and membrane topology. Science Report, 4, 6056.

    Article  CAS  Google Scholar 

  • Civinini, R., Capone, A., Carulli, C., Matassi, F., Nistri, L., & Innocenti, M. (2017). The kinetics of remodeling of calcium sulfate/calcium phosphate bioceramic. Journal of Materials Science: Materials in Medicine, 28(9), 137.

    PubMed  Google Scholar 

  • Cui, L., Zhuang, Q., Lin, J., et al. (2016). Multicentric epidemiologic study on six thousand three hundred and ninety five cases of femoral head osteonecrosis in China. International Orthopaedics, 40(2), 267–276.

    Article  PubMed  Google Scholar 

  • De Preter, V. (2015). Metabonomics and systems biology. Methods in Molecular Biology, 1277, 245–255.

    Article  CAS  PubMed  Google Scholar 

  • Glueck, C. J., Freiberg, R. A., & Wang, P. (2008). Heritable thrombophilia-hypofibrinolysis and osteonecrosis of the femoral head. Clinical Orthopaedics and Related Research, 466, 1034–1040.

    Article  PubMed  PubMed Central  Google Scholar 

  • Grauso, L., Mariggio, S., Corda, D., Fontana, A., & Cutignano, A. (2015). An improved UPLC–MS/MS platform for quantitative analysis of glycerophosphoinositol in mammalian cells. PLoS One, 10, e0123198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hernigou, P., Flouzat-Lachaniette, C. H., & Delambre, J. (2015). Osteonecrosis repair with bone marrow cell therapies: State of the clinical art. Bone, 70, 102–109.

    Article  PubMed  Google Scholar 

  • Herrmann, M., Widmann, T., & Herrmann, W. (2005). Homocysteine—A newly recognised risk factor for osteoporosis. Clinical Chemistry and Laboratory Medicine, 43, 1111–1117.

    CAS  PubMed  Google Scholar 

  • Hishikawa, D., Hashidate, T., Shimizu, T., & Shindou, H. (2014). Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells. Journal of Lipid Research, 55(5), 799–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holmes, E., Wilson, I. D., & Nicholson, J. K. (2008). Metabolic phenotyping in health and disease. Cell, 134, 714–717.

    Article  CAS  PubMed  Google Scholar 

  • Huang, C., & Freter, C. (2015). Lipid metabolism, apoptosis and cancer therapy. International Journal of Molecular Sciences, 16(1), 924–949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Issaq, H. J., Van, Q. N., Waybright, T. J., Muschik, G. M., & Veenstra, T. D. (2009). Analytical and statistical approaches to metabolomics research. Journal of Separation Science, 32, 2183–2199.

    Article  CAS  PubMed  Google Scholar 

  • Kang, P., Xie, X., Tan, Z., Yang, J., Shen, B., Zhou, Z., & Pei, F. (2015). Repairing defect and preventing collapse of femoral head in a steroid-induced osteonecrotic of femoral head animal model using strontiumdoped calcium polyphosphate combined BM-MNCs. Journal of Materials Science: Materials in Medicine, 26(2), 80.

    PubMed  Google Scholar 

  • Kilpinen, L., Tigistu-Sahle, F., Oja, S., et al. (2013). Aging bone marrow mesenchymal stromal cells have altered membrane glycerophospholipid composition and functionality. Journal of Lipid Research, 54(3), 622–635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, D. J., Koh, J. M., Lee, O., et al. (2006). Homocysteine enhances apoptosis in human bone marrow stromal cells. Bone, 39, 582–590.

    Article  CAS  PubMed  Google Scholar 

  • Klumpp, S., & Krieglstein, J. (2002). Phosphorylation and dephosphorylation of histidine residues in proteins. European Journal of Biochemistry, 269, 1067–1071.

    Article  CAS  PubMed  Google Scholar 

  • Koh, J. M., Lee, Y. S., Kim, Y. S., et al. (2006). Homocysteine enhances bone resorption by stimulation of osteoclast formation and activity through increased intracellular ROS generation. Journal of Bone and Mineral Research, 21(7), 1003–1011.

    Article  CAS  PubMed  Google Scholar 

  • Lee, J. S., Adler, L., Karathia, H., Carmel, N., Rabinovich, S., Auslander, N., & Keshet, R. (2018). Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures. Cell, 174(6), 1559–1570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, J. S., Roh, H. L., Kim, C. H., Jung, J. S., & Suh, K. T. (2006). Alterations in the differentiation ability of mesenchymal stem cells in patients with nontraumatic osteonecrosis of the femoral head: Comparative analysis according to the risk factor. Journal of Orthopaedic Research, 24, 604–609.

    Article  PubMed  Google Scholar 

  • Levasseur, R. (2008). Mechanisms of osteonecrosis. Joint Bone Spine, 75, 639–642.

    Article  PubMed  Google Scholar 

  • Lim, S. C., Duong, H. Q., Parajuli, K. R., & Han, S.I. (2012). Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. Oncology Report, 28(4), 1429–1434.

    Article  CAS  Google Scholar 

  • Liu, F., Wang, W., Yang, L., et al. (2017). An epidemiological study of etiology and clinical characteristics in patients with nontraumatic osteonecrosis of the femoral head. Journal of Research in Medical Sciences, 22, 15.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu, X., Li, Q., Sheng, J., Hu, B., et al. (2016). Unique plasma metabolomic signature of osteonecrosis of the femoral head. Journal of Orthopaedic Research, 34, 1158–1167.

    Article  PubMed  Google Scholar 

  • Loscalzo, J., Kohane, I., & Barabasi, A. L. (2007). Human disease classification in the postgenomic era: A complex systems approach to human pathobiology. Molecular Systems Biology, 3, 124.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mankin, H. J. (1992). Nontraumatic necrosis of bone (osteonecrosis). The New England Journal of Medicine, 326, 1473–1479.

    Article  CAS  PubMed  Google Scholar 

  • Moya-Angeler, J., Gianakos, A. L., Villa, J. C., Ni, A., & Lane, J. M. (2015). Current concepts on osteonecrosis of the femoral head. World Journal of Orthopedics, 6(8), 590–601.

    Article  PubMed  PubMed Central  Google Scholar 

  • Patti, G. J., Yanes, O., & Siuzdak, G. (2012). Innovation: metabolomics: The pogee of the omics trilogy. Nature Reviews Molecular Cell Biology, 13, 263–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Powell, C., Chang, C., & Gershwin, M. E. (2011). Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clinical Reviews in Allergy & Immunology, 41(1), 102–113.

    Article  CAS  Google Scholar 

  • Puchades-Carrasco, L., & Pineda-Lucena, A. (2015). Metabolomics in pharmaceutical research and development. Current Opinion in Biotechnology, 35, 73–77.

    Article  CAS  PubMed  Google Scholar 

  • Qiang, H., Liu, H., Ling, M., Wang, K., & Zhang, C. (2015). Early steroid-induced osteonecrosis of rabbit femoral head and Panax notoginseng saponins: Mechanism and protective effects. Evidence-Based Complementary and Alternative Medicine, 2015, 719370.

    Article  PubMed  PubMed Central  Google Scholar 

  • Qiao, L., Studer, E., Leach, K., et al. (2001). Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: Inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis. Mol Biol Cell, 12, 2629–2645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ragab, Y., Emad, Y., & Abou-Zeid, A. (2008). Bone marrow edema syndromes of the hip: mRI features in different hip disorders. Clinical Rheumatology, 27(4), 475–482.

    Article  PubMed  Google Scholar 

  • Schuhmacher, R., Krska, R., Weckwerth, W., & Goodacre, R. (2013). Metabolomics and metabolite profiling. Analytical and Bioanalytical Chemistry, 405, 5003–5004.

    Article  CAS  PubMed  Google Scholar 

  • Seito, N., Yamashita, T., Tsukuda, Y., et al. (2012). Interruption of glycerophospholipids synthesis enhances osteoarthritis development in mice. Arthritis & Rheumatology, 64(8), 2579–2588.

    Article  CAS  Google Scholar 

  • Shah, K. N., Racine, J., Jones, L. C., & Aaron, P. K. (2015). Pathophysiology and risk factors for osteonecrosis. Current Reviews in Musculoskeletal Medicine, 8, 201–209.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sionek, A., Czwojdziński, A., Kowalczewski, J., et al. (2018). Hip osteonecroses treated with calcium sulfate-calcium phosphate bone graft substitute have different results according to the cause of osteonecrosis: Alcohol abuse or corticosteroid-induced. International Orthopaedics, 42(7), 1491–1498.

    Article  PubMed  Google Scholar 

  • Slobogean, G. P., Sprague, S. A., Scott, T., & Bhandari, M. (2015). Complications following young femoral neck fractures. Injury, 46(3), 484–491.

    Article  CAS  PubMed  Google Scholar 

  • Snyder, M., & Li, X. Y. (2013). Metabolomics as a robust tool in systems biology and personalized medicine: An open letter to the metabolomics community. Metabolomics, 3, 532–534.

    Article  CAS  Google Scholar 

  • Steeg, P. S., Palmieri, D., Ouatas, T., & Salerno, M. (2003). Histidine kinases and histidine phosphorylated proteins in mammalian cell biology, signal transduction and cancer. Cancer Letter, 190(1), 11–12.

    Article  Google Scholar 

  • Stevens, K., Tao, C., Lee, S. U., et al. (2003). Subchondral fractures in osteonecrosis of the femoral head: Comparison of radiography, CT, and MR imaging. AJR American Journal of Roentgenology, 180, 363–368.

    Article  PubMed  Google Scholar 

  • Sugano, N., Kubo, T., & Takaoka, K. (1999). Diagnostic criteria for non-traumatic osteonecrosis of the femoral head: A multicentre study. Journal of Bone and Joint Surgery British, 81, 590–595.

    Article  CAS  Google Scholar 

  • Takarada, T., Takarada-Iemata, M., Takahata, Y., et al. (2012). Osteoclastogenesis is negatively regulated by d-serine produced by osteoblasts. Journal of Cellular Physiology, 227(10), 3477–3487.

    Article  CAS  PubMed  Google Scholar 

  • Tyagi, N., Kandel, M., Munjal, C., et al. (2011). Homocysteine mediated decrease in bone blood flow and remodeling: Role of folic acid. Journal of Orthopaedic Research, 29, 1511–1516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vijayan, V., Khandelwal, M., Manglani, K., Singh, R. R., Gupta, S., & Surolia, A. (2013). Homocysteine alters the osteoprotegerin/RANKL system in the osteoblast to promote bone loss: Pivotal role of the redox regulator forkhead O1. Free Radical Biology & Medicine, 61, 72–84.

    Article  CAS  Google Scholar 

  • Wang, H., Hu, P., & Jiang, J. (2012). Measurement of 1- and 3-methylhistidine in human urine by ultra performance liquid chromatography–tandem mass spectrometry. Clinica Chimica Acta, 413(1–2), 131–138.

    CAS  Google Scholar 

  • Wang, Y., Jones, P. J., Woollett, L. A., et al. (2006). Effects of chenodeoxycholic acid and deoxycholic acid on cholesterol absorption and metabolism in humans. Translational Research, 148(1), 37–45.

    Article  CAS  PubMed  Google Scholar 

  • Want, E. J., Wilson, I. D., Gika, H., et al. (2010). Global metabolic profiling procedures for urine using UPLC–MS. Nature Protocols, 5(6), 1005–1018.

    Article  CAS  PubMed  Google Scholar 

  • Wen, Z., Lin, Z., Yan, W., & Zhang, J. (2017). Influence of cigarette smoking on osteonecrosis of the femoral head (ONFH): A systematic review and meta-analysis. Hip International, 27(5), 425–435.

    Article  PubMed  Google Scholar 

  • Wilson, I. (2014). Tools for systems biology. Bioanalysis, 6(19), 2517–2518.

    Article  CAS  PubMed  Google Scholar 

  • Winder, C. L., Cornmell, R., Schuler, S., Jarvis, R. M., Stephens, G. M., & Goodacre, R. (2011). Metabolic fingerprinting as a tool to monitor whole-cell biotransformations. Analytical and Bioanalytical Chemistry, 399, 387–401.

    Article  CAS  PubMed  Google Scholar 

  • Wu, G. (2009). Amino acids: Metabolism, functions, and nutrition. Amino Acids, 37(1), 11–17.

    Google Scholar 

  • Xu, Z. W., Xu, K. M., Ding, S. J., et al. (2017). Serum metabolomic study for detecting biomarkers of non-traumatic osteonecrosis of the femoral head. Metabolomics, 13, 73.

    Article  CAS  Google Scholar 

  • Zalavras, C., Dailiana, Z., Elisaf, M., et al. (2000). Potential aetiological factors concerning the development of osteonecrosis of the femoral head. European Journal of Clinical Investigation, 30, 215–221.

    Article  CAS  PubMed  Google Scholar 

  • Zalavras, C. G., & Lieberman, J. R. (2014). Osteonecrosis of the femoral head: Evaluation and treatment. Journal of the American Academy of Orthopaedic Surgeons, 22(7), 455–464.

    Article  PubMed  Google Scholar 

  • Zhang, A., Sun, H., Wang, P., Han, Y., & Wang, X. (2012). Future perspectives of personalized medicine in traditional Chinese medicine: a systems biology approach. Complementary Therapies in Medicine, 20, 93–99.

    Article  PubMed  Google Scholar 

  • Zhu, W. W., Chen, T. M., Ding, S. J., et al. (2016). Metabolomic study of the bone trabecula of osteonecrosis femoral head patients based on UPLC–MS/MS. Metabolomics, 12, 48.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopedics, Fuling Center Hospital of Chongqing City, Chongqing, 408000, China

    Gang Yang, Gang Zhao & Yun Zhu

  2. Department of Orthopedics, The First Affiliated Hospital, Chongqing Medical University, Youyi Road No. 1, Chongqing, 400016, China

    Jian Zhang & Sichuan Gao

  3. Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China

    Tingmei Chen & Shijia Ding

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  1. Gang Yang
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  2. Gang Zhao
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  3. Jian Zhang
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Correspondence to Yun Zhu.

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Yang, G., Zhao, G., Zhang, J. et al. Global urinary metabolic profiling of the osteonecrosis of the femoral head based on UPLC–QTOF/MS. Metabolomics 15, 26 (2019). https://doi.org/10.1007/s11306-019-1491-8

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