类风湿性关节炎患者外周血T细胞RANKL增加且血清Dickkopf1降低
|
摘要
目的探讨骨代谢相关分子在类风湿性关节炎(RA)患者骨代谢异常和疾病进展过程中的作用。方法纳入RA患者66例及健康对照20例,搜集相关临床信息。利用电化学发光免疫分析法检测受试者血清中骨钙素N端中段(OC-N-MID)和1型胶原蛋白交联羧基末端肽(CTX)水平。采用液相悬浮芯片法检测Wnt抑制因子Dickkopf1(DKK1)、核因子κB受体激活蛋白配体(RANKL)含量。利用流式细胞术检测外周血T细胞上RANKL的水平。结果与健康对照组相比,RA患者血清中OC-N-MID、CTX含量无显著性差异,RANKL水平升高,DKK1水平降低。RA患者外周血T细胞上RANKL水平增加,尤其CD3+T细胞亚群上RANKL增加显著。结论 RA患者T细胞上RANKL水平增加,血清中RANKL含量升高,DKK1水平降低。
Objective To explore the roles of bone metabolism-related molecules in bone metabolic disturbance and disease progression of patients with rheumatoid arthritis( RA). Methods A total of 66 RA patients and 20 healthy controls were included,and their relevant clinical information was gathered. Electrochemiluminescence immunoassay( ECLIA) was used to detect the levels of osteocalcin N-terminal middle( OC-N-MID) and C-terminal cross-linked telopeptides of type 1collagen( CTX) in serum. The serum levels of Wnt inhibitory factor Dickkopf1( DKK1) and receptor activator of nuclear factor-κB ligand( RANKL) were determined by magnetic luminex assays. Flow cytometry was used to detect the RANKL level on peripheral blood T cells. Results Compared with healthy controls,the levels of OC-N-MID and CTX in the sera of the RA patients showed no significant difference. Level of RANKL in the sera of the RA patients was higher than that in the controls,while level of DKK1 was lower. The level of RANKL on peripheral blood T cells increased in the RA patients,especially on CD3+T cells. Conclusion In RA patients,level of RANKL on T cells is elevated,and the serum level of RANKL increases,but DKK1 decreases.
Objective To explore the roles of bone metabolism-related molecules in bone metabolic disturbance and disease progression of patients with rheumatoid arthritis( RA). Methods A total of 66 RA patients and 20 healthy controls were included,and their relevant clinical information was gathered. Electrochemiluminescence immunoassay( ECLIA) was used to detect the levels of osteocalcin N-terminal middle( OC-N-MID) and C-terminal cross-linked telopeptides of type 1collagen( CTX) in serum. The serum levels of Wnt inhibitory factor Dickkopf1( DKK1) and receptor activator of nuclear factor-κB ligand( RANKL) were determined by magnetic luminex assays. Flow cytometry was used to detect the RANKL level on peripheral blood T cells. Results Compared with healthy controls,the levels of OC-N-MID and CTX in the sera of the RA patients showed no significant difference. Level of RANKL in the sera of the RA patients was higher than that in the controls,while level of DKK1 was lower. The level of RANKL on peripheral blood T cells increased in the RA patients,especially on CD3+T cells. Conclusion In RA patients,level of RANKL on T cells is elevated,and the serum level of RANKL increases,but DKK1 decreases.
引文
[1]Tobón G J,Youinou P,Saraux A.The environment,geo-epidemiology,and autoimmunedisease:Rheumatoid arthritis[J].J Autoimmun,2010,35(1):10-14.
[2]Matuszewska A,Szechiński J.Mechanisms of osteoporosis development in patients with rheumatoid arthritis[J/OL].Postepy Hig Med Dosw(Online),2014,68:145-152.doi:10.5604/17322693.1088339.
[3]Peterson J C,Paget S A,Lachs M S,et al.The risk of comorbidity[J].Ann Rheum Dis,2012,71(5):635-637.
[4]Walsh N C,Gravallese E M.Bone remodeling in rheumatic disease:a question of balance[J].Immunol Rev,2010,233(1):301-312.
[5]Biliavska I,Stamm T A,Martinez-Avila J,et al.Application of the2010ACR/EULAR classification criteria in patients with very early inflammatory arthritis:analysis of sensitivity,specificity and predictive values in the SAVE study cohort[J].Ann Rheum Dis,2013,72(8):1335-1341.
[6]Khashayar P,Aghaei Meybodi H,Amoabediny G,et al.Biochemical markers of bone turnover and their role in osteoporosis diagnosis:A narrative review[J].Recent Pat Endocr Metab Immune Drug Discov,2015,9(2):79-89.
[7]Iwadate H,Kobayashi H,Kanno T,et al.Plasma osteopontin is correlated with bone resorption markers in rheumatoid arthritis patients[J].Int J Rheum Dis,2014,17(1):50-56.
[8]Fardellone P,SéjournéA,Paccou J,et al.Bone remodelling markers inrheumatoid arthritis[J/OL].Mediators Inflamm,2014,2014:484280.doi:10.1155/2014/484280.
[9]Zhao H,Han K L,Wang Z Y,et al.Value of C-telopeptide-cross-linked typeⅠcollagen,osteocalcin,bone-specific alkaline phosphatase and procollagen typeⅠN-terminal propeptide in the diagnosis and prognosis of bone metastasis in patients with malignant tumors[J].Med Sci Monit,2011,17(11):CR626-CR633.
[10]朱浪静,欧阳霞,郑东辉,等.类风湿关节炎患者滑膜TRAF6表达与血清骨代谢标志物的相关性[J].中华医学杂志,2014,94(21):1643-1646.
[11]Matuszewska A,Szechiński J.Evaluation of selected bone metabolism markers in rheumatoid arthritis patients[J].Adv Clin Exp Med,2013,22(2):193-202.
[12]DénariéD,Constant E,Thomas T,et al.Could biomarkers of bone,cartilage or synovium turnover be used for relapse prediction in rheumatoid arthritis patients[J/OL]?Mediators Inflamm,2014,2014:537324.doi:10.1155/2014/537324.
[13]Vis M,Havaardsholm E A,Haugeberg G,et al.Evaluation of bonemineral density,bone metabolism,osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis[J].Ann Rheum Dis,2006,65(11):1495-1499.
[14]Garnero P,Thompson E,Woodworth T,et al.Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate:results from a substudy of the multicenter double-blind,placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone[J].Arthritis Rheum,2010,62(1):33-43.
[15]Dougall W C.Molecular pathways:osteoclast-dependent and osteoclastindependent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis[J].Clin Cancer Res,2012,18(2):326-335.
[16]Yasuda H.RANKL,a necessary chance for clinical application to osteoporosis and cancer-related bone diseases[J].World J Orthop,2013,4(4):207-217.
[17]Xiong J,Piemontese M,Onal M,et al.Osteocytes,not osteoblasts or lining cells,are the main source of the RANKL required for osteoclast formation in remodeling bone[J/OL].PLoS One,2015,10(9):e0138189.doi:10.1371/journal.pone.0138189.eC ollection 2015.
[18]Motiur Rahman M,Takeshita S,Matsuoka K,et al.Proliferationcoupled osteoclast differentiation by RANKL:Cell density as a determinant of osteoclast formation[J].Bone,2015,81:392-399.
[19]Gendron S,Boisvert M,Chetoui N,et al.Alpha1beta1 integrin and interleukin-7 receptor up-regulate the expression of RANKL in human T cells and enhance their osteoclastogenic function[J].Immunology,2008,125(3):359-369.
[20]Kitaura H,Kimura K,Ishida M,et al.Effect of cytokines on osteoclast formation and bone resorption during mechanical force loading of the periodontal membrane[J/OL].ScientificW orld Journal,2014,2014:617032.doi:10.1155/2014/617032.eC ollection 2014.
[21]Kook S H,Jang Y S,Lee J C.Human periodontal ligament fibroblasts stimulate osteoclastogenesis in response to compression force through TNF-alpha-mediated activation of CD4+T cells[J].J Cell Biochem,2011,112(10):2891-2901.
[22]Kim H R,Kim K W,Kim B M,et al.Reciprocal activation of CD4+T cells and synovial fibroblasts by stromal cell-derived factor 1promotes RANKL expression and osteoclastogenesis in rheumatoid arthritis[J].Arthritis Rheumatol,2014,66(3):538-548.
[23]Goldring S R,Goldring M B.Eating bone or adding it:the Wnt pathway decides[J].Nat Med,2007,13(2):133-134.
[24]Tu X,Delgado-Calle J,Condon K W,et al.Osteocytes mediate the anabolic actions of canonical Wnt/beta-catenin signaling in bone[J/OL].Proc Natl Acad Sci U S A,2015,112(5):E478-E486.doi:10.1073/pnas.1409857112.Epub 2015 Jan 20.
[25]Zhou F,Meng S,Song H,et al.Dickkopf-1 is a key regulator of myeloma bone disease:opportunities and challenges for therapeutic intervention[J].Blood Rev,2013,27(6):261-267.
[26]Wang Y,Li Y P,Paulson C,et al.Wnt and the Wnt signaling pathway in bone development and disease[J].Front Biosci(Landmark Ed),2014,19:379-407.
[27]D’Alimonte I,Lannutti A,Pipino C,et al.Wnt signaling behaves as a“master regulator”in the osteogenic and adipogenic commitment of human amniotic fluid mesenchymal stem cells[J].Stem Cell Rev,2013,9(5):642-654.
[2]Matuszewska A,Szechiński J.Mechanisms of osteoporosis development in patients with rheumatoid arthritis[J/OL].Postepy Hig Med Dosw(Online),2014,68:145-152.doi:10.5604/17322693.1088339.
[3]Peterson J C,Paget S A,Lachs M S,et al.The risk of comorbidity[J].Ann Rheum Dis,2012,71(5):635-637.
[4]Walsh N C,Gravallese E M.Bone remodeling in rheumatic disease:a question of balance[J].Immunol Rev,2010,233(1):301-312.
[5]Biliavska I,Stamm T A,Martinez-Avila J,et al.Application of the2010ACR/EULAR classification criteria in patients with very early inflammatory arthritis:analysis of sensitivity,specificity and predictive values in the SAVE study cohort[J].Ann Rheum Dis,2013,72(8):1335-1341.
[6]Khashayar P,Aghaei Meybodi H,Amoabediny G,et al.Biochemical markers of bone turnover and their role in osteoporosis diagnosis:A narrative review[J].Recent Pat Endocr Metab Immune Drug Discov,2015,9(2):79-89.
[7]Iwadate H,Kobayashi H,Kanno T,et al.Plasma osteopontin is correlated with bone resorption markers in rheumatoid arthritis patients[J].Int J Rheum Dis,2014,17(1):50-56.
[8]Fardellone P,SéjournéA,Paccou J,et al.Bone remodelling markers inrheumatoid arthritis[J/OL].Mediators Inflamm,2014,2014:484280.doi:10.1155/2014/484280.
[9]Zhao H,Han K L,Wang Z Y,et al.Value of C-telopeptide-cross-linked typeⅠcollagen,osteocalcin,bone-specific alkaline phosphatase and procollagen typeⅠN-terminal propeptide in the diagnosis and prognosis of bone metastasis in patients with malignant tumors[J].Med Sci Monit,2011,17(11):CR626-CR633.
[10]朱浪静,欧阳霞,郑东辉,等.类风湿关节炎患者滑膜TRAF6表达与血清骨代谢标志物的相关性[J].中华医学杂志,2014,94(21):1643-1646.
[11]Matuszewska A,Szechiński J.Evaluation of selected bone metabolism markers in rheumatoid arthritis patients[J].Adv Clin Exp Med,2013,22(2):193-202.
[12]DénariéD,Constant E,Thomas T,et al.Could biomarkers of bone,cartilage or synovium turnover be used for relapse prediction in rheumatoid arthritis patients[J/OL]?Mediators Inflamm,2014,2014:537324.doi:10.1155/2014/537324.
[13]Vis M,Havaardsholm E A,Haugeberg G,et al.Evaluation of bonemineral density,bone metabolism,osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis[J].Ann Rheum Dis,2006,65(11):1495-1499.
[14]Garnero P,Thompson E,Woodworth T,et al.Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate:results from a substudy of the multicenter double-blind,placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone[J].Arthritis Rheum,2010,62(1):33-43.
[15]Dougall W C.Molecular pathways:osteoclast-dependent and osteoclastindependent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis[J].Clin Cancer Res,2012,18(2):326-335.
[16]Yasuda H.RANKL,a necessary chance for clinical application to osteoporosis and cancer-related bone diseases[J].World J Orthop,2013,4(4):207-217.
[17]Xiong J,Piemontese M,Onal M,et al.Osteocytes,not osteoblasts or lining cells,are the main source of the RANKL required for osteoclast formation in remodeling bone[J/OL].PLoS One,2015,10(9):e0138189.doi:10.1371/journal.pone.0138189.eC ollection 2015.
[18]Motiur Rahman M,Takeshita S,Matsuoka K,et al.Proliferationcoupled osteoclast differentiation by RANKL:Cell density as a determinant of osteoclast formation[J].Bone,2015,81:392-399.
[19]Gendron S,Boisvert M,Chetoui N,et al.Alpha1beta1 integrin and interleukin-7 receptor up-regulate the expression of RANKL in human T cells and enhance their osteoclastogenic function[J].Immunology,2008,125(3):359-369.
[20]Kitaura H,Kimura K,Ishida M,et al.Effect of cytokines on osteoclast formation and bone resorption during mechanical force loading of the periodontal membrane[J/OL].ScientificW orld Journal,2014,2014:617032.doi:10.1155/2014/617032.eC ollection 2014.
[21]Kook S H,Jang Y S,Lee J C.Human periodontal ligament fibroblasts stimulate osteoclastogenesis in response to compression force through TNF-alpha-mediated activation of CD4+T cells[J].J Cell Biochem,2011,112(10):2891-2901.
[22]Kim H R,Kim K W,Kim B M,et al.Reciprocal activation of CD4+T cells and synovial fibroblasts by stromal cell-derived factor 1promotes RANKL expression and osteoclastogenesis in rheumatoid arthritis[J].Arthritis Rheumatol,2014,66(3):538-548.
[23]Goldring S R,Goldring M B.Eating bone or adding it:the Wnt pathway decides[J].Nat Med,2007,13(2):133-134.
[24]Tu X,Delgado-Calle J,Condon K W,et al.Osteocytes mediate the anabolic actions of canonical Wnt/beta-catenin signaling in bone[J/OL].Proc Natl Acad Sci U S A,2015,112(5):E478-E486.doi:10.1073/pnas.1409857112.Epub 2015 Jan 20.
[25]Zhou F,Meng S,Song H,et al.Dickkopf-1 is a key regulator of myeloma bone disease:opportunities and challenges for therapeutic intervention[J].Blood Rev,2013,27(6):261-267.
[26]Wang Y,Li Y P,Paulson C,et al.Wnt and the Wnt signaling pathway in bone development and disease[J].Front Biosci(Landmark Ed),2014,19:379-407.
[27]D’Alimonte I,Lannutti A,Pipino C,et al.Wnt signaling behaves as a“master regulator”in the osteogenic and adipogenic commitment of human amniotic fluid mesenchymal stem cells[J].Stem Cell Rev,2013,9(5):642-654.