In Vivo Genome‐Wide Expression Study on Human Circulating B Cells Suggests a Novel ESR1 and MAPK3 Network for Postmenopausal Osteoporosis

: Osteoporosis is characterized by low BMD. Studies have shown that B cells may participate in osteoclastogenesis through expression of osteoclast‐related factors, such as RANKL, transforming growth factor β (TGFB), and osteoprotegerin (OPG). However, the in vivo significance of B cells in human bone metabolism and osteoporosis is still largely unknown, particularly at the systematic gene expression level. Materials and Methods : In this study, Affymetrix HG‐U133A GeneChip arrays were used to identify genes differentially expressed in B cells between 10 low and 10 high BMD postmenopausal women. Significance of differential expression was tested by t ‐test and adjusted for multiple testing with the Benjamini and Hochberg (BH) procedure (adjusted p ≤ 0.05). Results : Twenty‐nine genes were downregulated in the low versus high BMD group. These genes were further analyzed using Ingenuity Pathways Analysis (Ingenuity Systems). A network involving estrogen receptor 1 ( ESR1 ) and mitogen activated protein kinase 3 ( MAPK3 ) was identified. Real‐time RT‐PCR confirmed differential expression of eight genes, including ESR1 , MAPK3 , methyl CpG binding protein 2 ( MECP2 ), proline‐serine‐threonine phosphatase interacting protein 1 ( PSTPIP1 ), Scr ‐ like ‐ adaptor ( SLA ), serine / threonine kinase 11 ( STK11 ), WNK lysine‐deficient protein kinase 1 ( WNK1 ), and zinc finger protein 446 ( ZNF446 ). Conclusions : This is the first in vivo genome‐wide expression study on human B cells in relation to osteoporosis. Our results highlight the significance of B cells in the etiology of osteoporosis and suggest a novel mechanism for postmenopausal osteoporosis (i.e., that downregulation of ESR1 and MAPK3 in B cells regulates secretion of factors, leading to increased osteoclastogenesis or decreased osteoblastogenesis).