title: Quantitative proteomics and integrative network analysis identified novel genes and pathways related to osteoporosis.
abstract: Osteoporosis is mainly characterized by low bone mineral density (BMD), and can be attributed to excessive bone resorption by osteoclasts. Migration of circulating monocytes from blood to bone is important for subsequent osteoclast differentiation and bone resorption. Identification of those genes and pathways related to osteoclastogenesis and BMD will contribute to a better understanding of the pathophysiological mechanisms of osteoporosis. In this study, we applied the LC-nano-ESI-MS(E) (Liquid Chromatograph-nano-Electrospray Ionization-Mass Spectrometry) for quantitative proteomic profiling in 33 female Caucasians with discordant BMD levels, with 16 high vs. 17 low BMD subjects. Protein quantitation was accomplished by label-free measurement of total ion currents collected from MS(E) data. Comparison of protein expression in high vs. low BMD subjects showed that ITGA2B (p=0.0063) and GSN (p=0.019) were up-regulated in the high BMD group. Additionally, our protein-RNA integrative analysis showed that RHOA (p=0.00062) differentially expressed between high vs. low BMD groups. Network analysis based on multiple tools revealed two pathways: "regulation of actin cytoskeleton" (p=1.13E-5, FDR=3.34E-4) and "leukocyte transendothelial migration" (p=2.76E-4, FDR=4.71E-3) that are functionally relevant to osteoporosis. Consistently, ITGA2B, GSN and RHOA played crucial roles in these two pathways respectively. All together, our study strongly supported the contribution of the genes ITGA2B, GSN and RHOA and the two pathways to osteoporosis risk.
  
  
  
  Mass spectrometry based quantitative proteomics study integrated with network analysis identified novel genes and pathways related to osteoporosis. The results were further verified in multiple level studies including protein-RNA integrative analysis and genome wide association studies.
authors.affiliation: College of Life Sciences and Bioengineering, Beijing Jiao Tong University, Beijing 100044, China; Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA; College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: He
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA.
authors.forename: Ji-Gang
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA; Laboratory of Proteins and Proteomics, Department of Epidemiology, Soochow University School of Public Health, Suzhou 205123, Jiangsu, China.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Deng
authors.affiliation: College of Life Sciences and Bioengineering, Beijing Jiao Tong University, Beijing 100044, China.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Hu
authors.affiliation: College of Life Sciences and Bioengineering, Beijing Jiao Tong University, Beijing 100044, China.
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Zhang
authors.affiliation: College of Life Sciences and Bioengineering, Beijing Jiao Tong University, Beijing 100044, China; Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans 70112, LA, USA. Electronic address: hdeng2@tulane.edu.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D015519:Bone Density; D005260:Female; D018260:Gelsolin / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics*; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D009000:Monocytes / Q000737:chemistry; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000032:analysis; D040901:Proteomics / Q000379:methods*; D057705:Transendothelial and Transepithelial Migration; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D018260:Gelsolin; C056564:ITGA2B protein, human; D039421:Integrin alpha2; D020543:Proteome; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein
keywords: Network analysis; Osteoporosis; Pathways; Peripheral blood monocytes; Quantitative proteomics