Sun Yubo, Mauerhan David R, Steuerwald Nury M, Ingram Jane, Kneisl Jeffrey S, Hanley Edward N
Department of Orthopedic Surgery, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232, USA.
Molecular Biology Core, Cannon Research, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232, USA.
Biomed Res Int. 2014;2014:210469. doi: 10.1155/2014/210469. Epub 2014 Nov 23.
Phosphocitrate (PC) inhibited calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms remain elusive. This study sought to determine PC targeted genes and the expression of select PC targeted genes in OA menisci to test hypothesis that PC exerts its disease modifying activity in part by reversing abnormal expressions of genes involved in OA. We found that PC downregulated the expression of numerous genes classified in immune response, inflammatory response, and angiogenesis, including chemokine (C-C motif) ligand 5, Fc fragment of IgG, low affinity IIIb receptor (FCGR3B), and leukocyte immunoglobulin-like receptor, subfamily B member 3 (LILRB3). In contrast, PC upregulated the expression of many genes classified in skeletal development, including collagen type II alpha1, fibroblast growth factor receptor 3 (FGFR3), and SRY- (sex determining region Y-) box 9 (SOX-9). Immunohistochemical examinations revealed higher levels of FCGR3B and LILRB3 and lower level of SOX-9 in OA menisci. These findings indicate that OA is a disease associated with immune system activation and decreased expression of SOX-9 gene in OA menisci. PC exerts its disease modifying activity on OA, at least in part, by targeting immune system activation and the production of extracellular matrix and selecting chondroprotective proteins.
磷酸柠檬酸（PC）可抑制Hartley豚鼠中与钙晶体相关的骨关节炎（OA）。然而，其分子机制仍不清楚。本研究旨在确定PC的靶向基因以及OA半月板中选定的PC靶向基因的表达，以检验PC部分通过逆转OA相关基因的异常表达发挥其疾病修饰活性这一假设。我们发现PC下调了众多归类于免疫反应、炎症反应和血管生成的基因的表达，包括趋化因子（C-C基序）配体5、IgG的Fc片段、低亲和力IIIb受体（FCGR3B）和白细胞免疫球蛋白样受体亚家族B成员3（LILRB3）。相反，PC上调了许多归类于骨骼发育的基因的表达，包括II型胶原α1、成纤维细胞生长因子受体3（FGFR3）和SRY（性别决定区Y）-盒9（SOX-9）。免疫组织化学检查显示，OA半月板中FCGR3B和LILRB3水平较高，而SOX-9水平较低。这些发现表明，OA是一种与免疫系统激活以及OA半月板中SOX-9基因表达降低相关的疾病。PC至少部分通过靶向免疫系统激活、细胞外基质的产生以及选择软骨保护蛋白，对OA发挥其疾病修饰活性。
