~（99）Tc-MDP对胶原诱导性关节炎大鼠的治疗作用及对Wnt信号通路的影响
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摘要
目的：观察~(99)Tc-MDP对胶原诱导性关节炎(CIA)大鼠的骨保护作用及对Wnt信号通路的影响,探讨云克治疗RA的可能作用机制。
方法：随机选取6只SD大鼠作为正常组,余30只SD大鼠建立CIA模型。选取造模成功的SD大鼠18只随机分为模型组、~(99)Tc-MDP小剂量组和~(99)Tc-MDP大剂量组。在造模第14天开始分别进行对~(99)Tc-MDP治疗组予以2mg/kg·d和4mg/kg·d~(99)Tc-MDP尾静脉注射,正常组、模型组注射等体积生理盐水,共14天。肉眼观察足肿胀程度并进行关节炎指数评分,X线摄片及HE染色进行放射学和组织病理学评分。第29天处死所有大鼠,免疫组化检测关节局部Wnt5a、β-catenin、Lrp5表达,Real time-PCR检测滑膜中Wnt1、Wnt5a、P-catenin mRNA的表达。
结果：1.与模型组相比,~(99)Tc-MDP可以明显减轻CIA大鼠的关节肿胀,降低放射学评分和组织病理学评分。2.与模型组相比,~(99)Tc-MDP大小剂量治疗组β-catenin的表达增高,差异有统计学意义,而~(99)Tc-MDP不同剂量组比较没有差异。3.正常组大鼠关节区Wnt5a阳性细胞数较少,模型组及大小剂量~(99)Tc-MDP组表达亦较低,各组均无显著性差异。与正常组相比,模型组大鼠骨质区Lrp5阳性细胞相对较多,但无统计学差异。与模型组相比,~(99)Tc-MDP各治疗组Lrp5表达无显著性差异。4.与正常组比,模型组和~(99)Tc-MDP大小剂量治疗组大鼠滑膜组织中Wnt1、p-catenin、Wnt5a mRNA表达均未发现有统计学差异。
结论：1.~(99)Tc-MDP对CIA大鼠有明确的关节保护作用。2.~(99)Tc-MDP对CIA大鼠的关节保护作用可能与其调节Wnt信号通路中的β-catenin蛋白表达有关,这可能是其治疗RA的作用机制之一。3.~(33)Tc-MDP对CIA大鼠的关节保护作用与Wnt1、Wnt5a及Lrp5的表达无关。
Objective:To determine the jionts protection of 99Tc-MDP in collagen-induced arthritis rats model and its effect on Wnt signaling pathway, and explore the possible treatment mechanism of 99Tc-MDP in rheumatoid arthritis(RA).
Methods:Selected 6 SD rats randomly as normal group, the others were immunized with an emulsion of collagen.18 CIA rats were randomly divided into 3 groups:Normal group and CIA model group receiving saline water, low dose 99Tc-MDP treatment group(2mg/kg·d) and high dose 99Tc-MDP treatment group(4mg/kg·d). totall 14days, Paw inflammation was assessed by arthritis index. Lesions of bone and cartilage were evaluated on the basis of histological change in ankle joint, radiographic analysis in hind paw with X ray by Larsen score. All rats were killed on day 29, immunohistochemical detection of joints local Wnt5a,β-catenin, Lrp5 expression, The expression of Wnt1、Wnt5a、β-catenin mRNA in synovium was analyzed by real time-PCR.
Results:1. The arthritis index and mean radiographic scores were significantly lower in 99Tc-MDP treatment groups than in CIA model group. Histological analysis confirmed the suppression of joint inflammation and showed prevention of cartilage and bone destruction after treatment of 99Tc-MDP.2. Both 99Tc-MDP treatment groups expression ofβ-catenin increased significantly contrast to the model, but there is not different between both treatment groups.3. normal group rats joints areas show fewer Wnt5a positive cells, the expression is also lower in model group and of 99Tc-MDP group, there is no significant difference among the four groups. Compared with normal rats, the positive expression of Lrp5 is visible in model group bone areas, but there is no significant difference. Lrp5 showed no significant difference in 99Tc-MDP group contrast to model group.4. Compared with the normal group, the lever of Wnt1, Wnt5a,β-catenin mRNA are not different in Synovial tissue among model group and both 99Tc-MDP groups, show no significant difference.
Conclusion:1.99Tc-MDP offered a significant joint protection in CIA rats.2.The effects of 99Tc-MDP on the CIA rats may be related to its regulation of (3-catenin protein in Wnt signaling pathway. It may be one of the effective mechanism in the treatment of RA.3. the joint protection of99Tc-MDP is independent with the expression of Wntl,Wnt5a and Lrp5 in CIA rats.
方法：随机选取6只SD大鼠作为正常组,余30只SD大鼠建立CIA模型。选取造模成功的SD大鼠18只随机分为模型组、~(99)Tc-MDP小剂量组和~(99)Tc-MDP大剂量组。在造模第14天开始分别进行对~(99)Tc-MDP治疗组予以2mg/kg·d和4mg/kg·d~(99)Tc-MDP尾静脉注射,正常组、模型组注射等体积生理盐水,共14天。肉眼观察足肿胀程度并进行关节炎指数评分,X线摄片及HE染色进行放射学和组织病理学评分。第29天处死所有大鼠,免疫组化检测关节局部Wnt5a、β-catenin、Lrp5表达,Real time-PCR检测滑膜中Wnt1、Wnt5a、P-catenin mRNA的表达。
结果：1.与模型组相比,~(99)Tc-MDP可以明显减轻CIA大鼠的关节肿胀,降低放射学评分和组织病理学评分。2.与模型组相比,~(99)Tc-MDP大小剂量治疗组β-catenin的表达增高,差异有统计学意义,而~(99)Tc-MDP不同剂量组比较没有差异。3.正常组大鼠关节区Wnt5a阳性细胞数较少,模型组及大小剂量~(99)Tc-MDP组表达亦较低,各组均无显著性差异。与正常组相比,模型组大鼠骨质区Lrp5阳性细胞相对较多,但无统计学差异。与模型组相比,~(99)Tc-MDP各治疗组Lrp5表达无显著性差异。4.与正常组比,模型组和~(99)Tc-MDP大小剂量治疗组大鼠滑膜组织中Wnt1、p-catenin、Wnt5a mRNA表达均未发现有统计学差异。
结论：1.~(99)Tc-MDP对CIA大鼠有明确的关节保护作用。2.~(99)Tc-MDP对CIA大鼠的关节保护作用可能与其调节Wnt信号通路中的β-catenin蛋白表达有关,这可能是其治疗RA的作用机制之一。3.~(33)Tc-MDP对CIA大鼠的关节保护作用与Wnt1、Wnt5a及Lrp5的表达无关。
Objective:To determine the jionts protection of 99Tc-MDP in collagen-induced arthritis rats model and its effect on Wnt signaling pathway, and explore the possible treatment mechanism of 99Tc-MDP in rheumatoid arthritis(RA).
Methods:Selected 6 SD rats randomly as normal group, the others were immunized with an emulsion of collagen.18 CIA rats were randomly divided into 3 groups:Normal group and CIA model group receiving saline water, low dose 99Tc-MDP treatment group(2mg/kg·d) and high dose 99Tc-MDP treatment group(4mg/kg·d). totall 14days, Paw inflammation was assessed by arthritis index. Lesions of bone and cartilage were evaluated on the basis of histological change in ankle joint, radiographic analysis in hind paw with X ray by Larsen score. All rats were killed on day 29, immunohistochemical detection of joints local Wnt5a,β-catenin, Lrp5 expression, The expression of Wnt1、Wnt5a、β-catenin mRNA in synovium was analyzed by real time-PCR.
Results:1. The arthritis index and mean radiographic scores were significantly lower in 99Tc-MDP treatment groups than in CIA model group. Histological analysis confirmed the suppression of joint inflammation and showed prevention of cartilage and bone destruction after treatment of 99Tc-MDP.2. Both 99Tc-MDP treatment groups expression ofβ-catenin increased significantly contrast to the model, but there is not different between both treatment groups.3. normal group rats joints areas show fewer Wnt5a positive cells, the expression is also lower in model group and of 99Tc-MDP group, there is no significant difference among the four groups. Compared with normal rats, the positive expression of Lrp5 is visible in model group bone areas, but there is no significant difference. Lrp5 showed no significant difference in 99Tc-MDP group contrast to model group.4. Compared with the normal group, the lever of Wnt1, Wnt5a,β-catenin mRNA are not different in Synovial tissue among model group and both 99Tc-MDP groups, show no significant difference.
Conclusion:1.99Tc-MDP offered a significant joint protection in CIA rats.2.The effects of 99Tc-MDP on the CIA rats may be related to its regulation of (3-catenin protein in Wnt signaling pathway. It may be one of the effective mechanism in the treatment of RA.3. the joint protection of99Tc-MDP is independent with the expression of Wntl,Wnt5a and Lrp5 in CIA rats.
引文
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[1]Eberhardt K., B. M. Larsson, K. Nived, et al. Work disability in rheumatoid arthritis--development over 15 years and evaluation of predictive factors over time. J Rheumatol,2007,34(3):481-487.
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[22]Tanaka I., M. Morikawa, T. Okuse, et al. Expression and regulation of WISP2 in rheumatoid arthritic synovium. Biochem Biophys Res Commun,2005,334 (4):973-978.
[23]Cheon H., D. L. Boyle, and G. S. Firestein. Wntl inducible signaling pathway protein-3 regulation and microsatellite structure in arthritis. J Rheumatol,2004, 31(11):2106-2114.
[24]Sen M., K. Lauterbach, H. El-Gabalawy, et al. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci U S A,2000,97(6):2791-2796.
[25]Nakamura Y., M. Nawata, and S. Wakitani. Expression profiles and functional analyses of Wnt-related genes in human joint disorders. Am J Pathol,2005, 167(1):97-105.
[26]Imai K., M. Morikawa, J. D'Armiento, et al. Differential expression of WNTs and FRPs in the synovium of rheumatoid arthritis and osteoarthritis. Biochem Biophys Res Commun,2006,345(4):1615-1620.
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[30]Schett G., J. Zwerina, and J. P. David. The role of Wnt proteins in arthritis. Nat Clin Pract Rheumatol,2008,4(9):473-480.
[31]Shi Y. C., L. Worton, L. Esteban, et al. Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation. Bone,2007,41(1):87-96.
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[33]Rabelo Fde S., L. M. da Mota, R. A. Lima, et al. The Wnt signaling pathway and rheumatoid arthritis. Autoimmun Rev,9(4):207-210.
[34]Hill T. P., D. Spater, M. M. Taketo, et al. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell,2005, 8(5):727-738.
[35]Koay M. A. and M. A. Brown. Genetic disorders of the LRP5-Wnt signalling pathway affecting the skeleton. Trends Mol Med,2005,11(3):129-137.
[36]Babij P., W. Zhao, C. Small, et al. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res,2003,18(6):960-974.
[37]Levasseur R., D. Lacombe, and M. C. de Vernejoul. LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Joint Bone Spine,2005,72(3):207-214.
[38]Pinzone J. J., B. M. Hall, N. K. Thudi, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood,2009,113(3):517-525.
[39]Bodine P. V. and B. S. Komm. Wnt signaling and osteoblastogenesis. Rev Endocr Metab Disord,2006,7(1-2):33-39.
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[2]Damjanov N. and J. Vojinovic. [Biologic therapy of rheumatoid arthritis]. Srp Arh Celok Lek,2009,137(3-4):205-210.
[3]Schett G. and S. L. Teitelbaum. Osteoclasts and arthritis. J Bone Miner Res, 2009,24(7):1142-1146.
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