title: Peripheral blood monocyte-expressed ANXA2 gene is involved in pathogenesis of osteoporosis in humans.
abstract: Low bone mineral density (BMD) is a risk factor of osteoporosis and has strong genetic determination. Genes influencing BMD and fundamental mechanisms leading to osteoporosis have yet to be fully determined. Peripheral blood monocytes (PBM) are potential osteoclast precursors, which could access to bone resorption surfaces and differentiate into osteoclasts to resorb bone. Herein, we attempted to identify osteoporosis susceptibility gene(s) and characterize their function(s), through an initial proteomics discovery study on PBM in vivo, and multiscale validation studies in vivo and in vitro. Utilizing the quantitative proteomics methodology LC-nano-ESI-MS(E), we discovered that a novel protein, i.e. ANXA2, was up-regulated twofold in PBM in vivo in Caucasians with extremely low BMD (cases) versus those with extremely high BMD (controls) (n = 28, p < 0.05). ANXA2 gene up-regulation in low BMD subjects was replicated at the mRNA level in PBM in vivo in a second and independent case-control sample (n = 80, p < 0.05). At the DNA level, we found that SNPs in the ANXA2 gene were associated with BMD variation in a 3(rd) and independent case-control sample (n = 44, p < 0.05), as well as in a random population sample (n = 997, p < 0.05). The above integrative evidence strongly supports the concept that ANXA2 is involved in the pathogenesis of osteoporosis in humans. Through a follow-up cellular functional study, we found that ANXA2 protein significantly promoted monocyte migration across an endothelial barrier in vitro (p < 0.001). Thus, elevated ANXA2 protein expression level, as detected in low BMD subjects, probably stimulates more PBM migration through the blood vessel walls to bone resorption surfaces in vivo, where they differentiate into higher number of osteoclasts and resorb bone at higher rates, thereby decreasing BMD. In conclusion, this study identified a novel osteoporosis susceptibility gene ANXA2, and suggested a novel pathophysiological mechanism, mediated by ANXA2, for osteoporosis in humans.
authors.affiliation: Center of Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Deng
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Lei
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Zhang
authors.forename: Yan-Peng
authors.initials: YP
authors.lastname: Zheng
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Pan
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Yunxia Wang
authors.initials: YW
authors.lastname: Lundberg
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D000328:Adult; D000368:Aged; D017306:Annexin A2 / Q000235:genetics* / Q000378:metabolism; D015519:Bone Density; D016022:Case-Control Studies; D005260:Female; D005272:Femur Neck / Q000473:pathology; D015870:Gene Expression; D056726:Genetic Association Studies; D006615:Hip / Q000473:pathology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D057705:Transendothelial and Transepithelial Migration; D015854:Up-Regulation
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2