Peripheral Blood Monocyte-expressed ANXA2 Gene is Involved in Pathogenesis of Osteoporosis in Humans

• Published in: Molecular & cellular proteomics Vol. 10; no. 11; pp. M111 - M111.011700
• Main Authors: Deng, Fei-Yan, Lei, Shu-Feng, Zhang, Yan, Zhang, Yu-Ling, Zheng, Yan-Peng, Zhang, Li-Shu, Pan, Rong, Wang, Lili, Tian, Qing, Shen, Hui, Zhao, Ming, Lundberg, Yunxia Wang, Liu, Yao-Zhong, Papasian, Christopher J., Deng, Hong-Wen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2011; The American Society for Biochemistry and Molecular Biology
• Subjects: Adult; Aged; Annexin A2 - genetics; Annexin A2 - metabolism; Blood vessels; Bone Density; Bone mineral density; Bone resorption; Case-Control Studies; DNA; Female; Femur Neck - pathology; Gene Expression; Genetic Association Studies; Hemopoiesis; Hip - pathology; Humans; Leukocyte migration; Leukocytes, Mononuclear - metabolism; Middle Aged; Monocytes; mRNA; Osteoclasts; Osteoporosis; Osteoporosis - genetics; Osteoporosis - physiopathology; Osteoprogenitor cells; Peripheral blood; Polymorphism, Single Nucleotide; proteomics; Risk factors; Single-nucleotide polymorphism; Stem cells; Transendothelial and Transepithelial Migration; Up-Regulation
• ISSN: 1535-9476; 1535-9484; 1535-9484
• DOI: 10.1074/mcp.M111.011700

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-MSE, 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 3rd 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.