title: BDKRB2 +9/-9 bp polymorphisms influence BDKRB2 expression levels and NO production in knee osteoarthritis.
abstract: The bradykinin B2 receptor (BDKRB2) plays a key role in the inflammation process of osteoarthritis. Nitric oxide has also long been considered to be a catabolic factor that contributes to inflammatory response and the osteoarthritis disease pathology. Several studies have reported that the BDKRB2 +9/-9 bp polymorphisms are associated with transcription of the receptor. However, the roles of BDKRB2 polymorphisms in inflammation in osteoarthritis remain unclear. This study enrolled 156 subjects with primary knee osteoarthritis and 58 healthy volunteers. BDKRB2 polymorphisms were genotyped, and the mRNA and protein levels of BDKRB2 in synovial tissues from osteoarthritis patients were measured by quantitative real-time polymerase chain reaction and western blot analysis, respectively. Nitric oxide production in serum from patients with osteoarthritis was measured using a nitric oxide assay kit. We found that the mean BDKRB2 mRNA levels were significantly higher in Kallgren-Lawrence grade-4 osteoarthritis patients than patients with lower grade osteoarthritis. The +9/-9 bp polymorphisms significantly affected the BDKRB2 mRNA and protein expression levels in synovial tissues from osteoarthritis subjects. Osteoarthritis patients with +9/-9 and -9/-9 genotypes had higher BDKRB2 expression levels in synovial tissue and nitric oxide production in serum. Moreover, positive correlation was found between the BDKRB2 levels in synovial tissue and nitric oxide production. Compared with health controls, significant increases of nitric oxide production in osteoarthritis were detected which were associated with increasing severity of osteoarthritis. Multiple linear regression analysis (adjusted for gender and age) showed serum nitric oxide level was positively associated with BDKRB2 polymorphism and Kallgren-Lawrence grade and was inversely associated with obesity. Our findings showed that the BDKRB2 +9/-9 bp polymorphisms affected the gene expression and nitric oxide production, which were associated with radiographic severity of osteoarthritis, suggesting that the BDKRB2 +9/ -9 bp polymorphisms may act as a genetic modulator of osteoarthritis, and play an essential role in inflammatory process in osteoarthritis.
authors.affiliation: 1 Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.affiliation: 1 Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 2 Offices of Health Care, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Ruonan
authors.initials: R
authors.lastname: Xu
authors.affiliation: 1 Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Yunfan
authors.initials: Y
authors.lastname: Ti
authors.affiliation: 3 Department of Orthopedics, School of Clinical Medicine, Nanjing University, Nanjing 210000, China The first two authors contributed equally to this work.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 1 Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Liwu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 1 Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood* / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000473:pathology*; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043782:Receptor, Bradykinin B2 / Q000235:genetics* / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology*
chemical_list: D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D009569:Nitric Oxide
keywords: Bradykinin B2 Receptor (BDKRB2); gene polymorphisms; inflammation; osteoarthritis (OA)