骨保护蛋白和骨保护蛋白配体与脊柱结核病灶骨硬化关系的研究
摘要
目的通过研究脊柱结核病灶骨不同部位的骨保护蛋白(OPG)和骨保护蛋白配体(OPGL)的表达情况以及与平均CT值的关系,揭示OPG和OPGL参与脊柱结核的病理过程和意义,从分子水平深化对脊柱结核病灶骨硬化发生机制的认识,为阐明脊柱结核病灶骨硬化发生机制提供新的线索;初步探讨脊柱结核病灶骨硬化的病理结构;为脊柱结核的临床诊断和治疗提供新的理论依据。方法2007年5月～2008年10月,宁夏医科大学附属医院骨科手术治疗并经病理学检查确诊的38例脊柱结核患者。其中男性20例,女性18例,年龄14～72岁,平均年龄46岁。胸椎9例,胸腰段11例,腰椎18例。取脊柱结核术中切除的骨质,按照部位分为三组,紧挨病灶空洞壁的为硬化骨组,以椎体病灶为中心,向外达到正常的骨质为正常骨组,位于硬化骨和正常骨之间的为亚正常骨组。如果术中没有硬化骨,则取正常骨质与病灶空洞壁之间的部分作为亚正常骨组。利用HE染色进行骨组织形态学观察。利用PV-6000二步法免疫组化检测技术研究病灶骨各部位OPG和OPGL的表达情况,光镜下观察,每张切片随机选取5个不相重复的视野采集图像,并将图像输人图像分析系统,测定OPG和OPGL免疫组化染色平均光密度,阳性面积比,取每张切片的均值作为该例的测量值。CT值的测量:根据患者术前检查的CT用骨窗对病灶部位进行观察,测量每个病例每一部位的平均CT值。利用SPSS11.5统计分析软件进行单因素方差分析和Pearson相关分析。P>0.05认为差异无统计学意义, P <0.05认为差异有统计学意义,P <0.01认为差异有显著统计学意义。结果硬化骨组OPG平均光密度、阳性面积比以及OPG和OPGL表达的比值均明显高于亚正常骨组和正常骨组,差异有显著统计学意义(P<0.01);硬化骨组OPGL平均光密度、阳性面积比以及平均CT值均高于亚正常骨组和正常骨组,差异有统计学意义(P<0.05);各组OPG和OPGL平均光密度、阳性面积比以及OPG和OPGL表达的比值均与平均CT值呈正相关关系。硬化骨组钙化发生率为17.24%。结论脊柱结核病灶骨在修复转化过程中产生了硬化骨,硬化骨的产生与OPG和OPGL在病灶骨组织中不同程度的表达相关。硬化骨组内OPG和OPGL的表达程度增强,且两者均与平均CT值之间存在正相关关系,推测OPG和OPGL可能在脊柱结核病灶骨质硬化的发生中发挥重要作用,硬化骨组OPG和OPGL表达的比值明显高于亚正常骨组和正常骨组,推测在脊柱结核病灶骨发生硬化的病理过程中,OPG和OPGL均处于高表达状态,只是由于OPG的表达更高于OPGL的表达而导致了脊柱结核病灶骨组织硬化的发生。硬化骨的病理结构可能以高密度骨化为主,部分病例为骨化与钙化并存。
Objective To explain the role of OPG and OPGL in the pathological process of spinal tuberculosis and its relation to CT through studying the expression of OPG and OPGL in different section of spinal tubercular infectious focus. To approach primarily pathological structure and molecular mechanism of the indurascent focus of spinal tuberculosis so as to provide original theory for pathological mechanism and clinical diagnosis and treatment of spinal tuberculosis. Methods From May of 2007 to October of 2008, the Orthopaedics of Affiliated Hospital of Ningxia Medical University, 38 operated patients were diagnosed as spinal tuberculosis through clinical symptoms and signs and post-operation pathological results. 20patients are male and 18 are female, the age ranged from 14 to 72, average is 46 years old. 9 patients were thoracic spinal TB, 11 were thoracic-lumbar TB and 18 lower-lumbar TB. The resected bones were divided into 3 groups based on their regions, the ossified bones were located at surrounding of infectious focus of spinal tuberculosis, normal bones were most distant from the focus, non-ossified bones were located between the above 2 groups. To observe structure of bone tissue in the different group according to HE- staining. To examine the expression of OPG and OPGL in the different group by means of PV-6000 two-step immunochemistry technique. After immunohistochemical staining, to analyze 5 random fields for each section. The mean optical density and percent of positive area were measured using computer-assisted image analysis system. The mean CT value of every section was measure. Statistical analysis method: One-way ANOVA and Pearson correlation were performed with SPSS11.5 software package. There is notable significant difference statistically(P<0.01), there is significant difference statistically(P<0.05) while there are not significant difference statistically(P>0.05). Results Results demonstrated that the mean optical density and percent of positive area of staining of OPG and OPGL, ratio of their expression, and the mean CT value were not consistent in different groups. Expression of OPG and OPGL, and ratio of their expressions were significantly enhanced in ossified group than both in non-ossified group and normal group(P<0.05). The mean CT value was significantly higher in ossified group than both in non-ossified group and normal group(P<0.05). There was positively significant relationgship between expressions of OPG and the mean CT value(P<0.05). There was positively significant relationgship between expressions of OPGL and the mean CT value(P<0.05). There was positively significant relationgship between ratio of their expressions and the mean CT value(P<0.05). percentage of pathologic calcification from ossified group is 17.24%. Conclusions There were different levels of expression of OPG and OPGL which relate to ossified bone in the focus of spinal tuberculosis. With accordance to the above results , we can come to the conclusion that OPG might play an important role with OPGL together in the process of bone changes in spinal tuberculosis, their expression was promoted respectively while expression of OPG was higher than expression of OPGL, which led to ossified bone in spinal tuberculosis. High-density pathological structure of Indurascent Focus of Spinal Tuberculosis mainly is ossification, the other fraction is concomitance of ossification and calcification.
Objective To explain the role of OPG and OPGL in the pathological process of spinal tuberculosis and its relation to CT through studying the expression of OPG and OPGL in different section of spinal tubercular infectious focus. To approach primarily pathological structure and molecular mechanism of the indurascent focus of spinal tuberculosis so as to provide original theory for pathological mechanism and clinical diagnosis and treatment of spinal tuberculosis. Methods From May of 2007 to October of 2008, the Orthopaedics of Affiliated Hospital of Ningxia Medical University, 38 operated patients were diagnosed as spinal tuberculosis through clinical symptoms and signs and post-operation pathological results. 20patients are male and 18 are female, the age ranged from 14 to 72, average is 46 years old. 9 patients were thoracic spinal TB, 11 were thoracic-lumbar TB and 18 lower-lumbar TB. The resected bones were divided into 3 groups based on their regions, the ossified bones were located at surrounding of infectious focus of spinal tuberculosis, normal bones were most distant from the focus, non-ossified bones were located between the above 2 groups. To observe structure of bone tissue in the different group according to HE- staining. To examine the expression of OPG and OPGL in the different group by means of PV-6000 two-step immunochemistry technique. After immunohistochemical staining, to analyze 5 random fields for each section. The mean optical density and percent of positive area were measured using computer-assisted image analysis system. The mean CT value of every section was measure. Statistical analysis method: One-way ANOVA and Pearson correlation were performed with SPSS11.5 software package. There is notable significant difference statistically(P<0.01), there is significant difference statistically(P<0.05) while there are not significant difference statistically(P>0.05). Results Results demonstrated that the mean optical density and percent of positive area of staining of OPG and OPGL, ratio of their expression, and the mean CT value were not consistent in different groups. Expression of OPG and OPGL, and ratio of their expressions were significantly enhanced in ossified group than both in non-ossified group and normal group(P<0.05). The mean CT value was significantly higher in ossified group than both in non-ossified group and normal group(P<0.05). There was positively significant relationgship between expressions of OPG and the mean CT value(P<0.05). There was positively significant relationgship between expressions of OPGL and the mean CT value(P<0.05). There was positively significant relationgship between ratio of their expressions and the mean CT value(P<0.05). percentage of pathologic calcification from ossified group is 17.24%. Conclusions There were different levels of expression of OPG and OPGL which relate to ossified bone in the focus of spinal tuberculosis. With accordance to the above results , we can come to the conclusion that OPG might play an important role with OPGL together in the process of bone changes in spinal tuberculosis, their expression was promoted respectively while expression of OPG was higher than expression of OPGL, which led to ossified bone in spinal tuberculosis. High-density pathological structure of Indurascent Focus of Spinal Tuberculosis mainly is ossification, the other fraction is concomitance of ossification and calcification.
引文
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[6] Kostenuik PJ, Shalboub V. Osteoprotegerin: a physiological and pharmacological inhibitory of bone resorptiontion[J]. Curr pharm Des, 2001, 7(8): 613-635.
[7]张莹,钱聪.骨保护蛋白与慢性氟中毒大鼠骨质硬化关系的研究[D].中国医科大学, 2005. 22-24.
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[12] Hasegawa T, Yoshimura Y, Kikuiri T, et al. Expression of receptor acti-vator of NF-kappa B ligand and osteoprotegerin in culture of human pe-riodontal ligament cells[J]. J Periodontal Res, 2002, 37(6): 405-411.
[13] Matsuzak K, Udagawa N, Takahashi N,et al. Osteoclast differentiation factor(ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures[J]. Biochem Biophys Res Commun, 1998, 246: 199-204.
[14] Kong YY, Yoshida, Sarosi T, et al. OPGL is a key regulator or osteoclastogenesis, lymphocyte development and lymph-node organogenesis[J]. Nature, 1999, 397: 315-323.
[15] Romas E, Sims NA, Hards DK, et al. Osteoprotegerin reduces osteoclastnumbers and preventsboneerosionincollagen-induced arthritis[J]. Am J Pathol, 2002, 161(4): 14 19-1427.
[16] Suda T. How is bone formed and resorbed?-molecular mechanisms of bone formation and resorption[J]. Biosho Byori, 2002, 50(3): 267-272.
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[18] Teitelbaum SL. Bone resorption by osteoclasts[J]. Science, 2000, 89(5484): 1504-1508.
[19] Liu XH, Kirschenbaum A, Yao S, et al. Interactive effect of interleukin-6 and prostaglandin E2 on osteoclastogenesis via the OPG/RANKL/RANK system[J]. Ann N Y Acad Sci, 2006, 1068: 225-233.
[20] Shevde NK, Bendixen AC, Dienger KM, et al. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression[J]. Proc Natl Acad Sci USA, 2000, 97(14): 7829-7834.
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[23] Makrygiannakis D, af Klint E, Catrina SB, et al. Intraarticular corticosteroids decrease synovial RANKL expression in inflammatory arthritis[J]. Arthritis Rheum, 2006, 54(5): 1463-1472.
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[25] Kanzaki H, Chiba M, AraiK, et al. LocalRANKL gene trans-fer to the periodontal tissue accelerates orthodontic tooth movement[J]. GeneTher, 2006, 13(8): 678-685.
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[1] Palmqviet P, Persson W, Conaway HH, et al. IL-6, leukemia inhibitoty factor, and Oncostati M stimulate bone resorption and regulate the expression of receptor of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae[J]. J Immunol, 2002, 169: 3353-3362.
[2] Simonet WS, Lacey DL, Dunsnat, etal. osteoporetgerin: A novel secreted protein involed in the regulation of bone density[J]. Cell, 1997, 89: 309-319
[3] Tsuda E,Goto M,Mochizuki S,et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoeclastogenesis[J]. Bioehem BioPhys Res Commun, 1997, 234: 137一142.
[4] Yasuda H, Shima N, Nakagawa N, et al. Identiy of osteoclastogenesis inhib-Itory factor(OCIF) and osteoprotegerin(OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in viotr[J]. Endocrinology, 1998, 39: 1329-1337.
[5] Udagawa N,Takhaashi N,YasudaH,et al. osteoprotegerin porduced by osteoblasts is an important regulator in osteoclast development and function [J]. Endocrinology, 2000, 141: 3478一3483.
[6] Kostenuik PJ, Shalboub V. Osteoprotegerin: a physiological and pharmacological inhibitory of bone resorptiontion[J]. Curr pharm Des, 2001, 7(8): 613-635.
[7]张莹,钱聪.骨保护蛋白与慢性氟中毒大鼠骨质硬化关系的研究[D].中国医科大学, 2005. 22-24.
[8]范蓬,周健,唐丽丽,等.骨保护素及其配体在牙正畸中作用的研究进展[J].医学综述, 2007, 13(8): 605-607.
[9] Yasuda H, Shima N, Nakagawa N, et al. osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL [J]. Proc Natl Acad Sci USA, 1998, 95(7): 3597-3602.
[10] Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin(OPG) Ligand is a cytokine that regulates osteoclast differentiation and activation[J]. cell, 1998, 93: 165- 176.
[11] Malyankar UM, Scatena M, Suchland KL, et al. OsteoProtegerin is an avβ3-induced, NF-kB-dependent survival factor for endothelial cells[J]. J Biol Chem, 2000, 275: 20959-20962.
[12] Hasegawa T, Yoshimura Y, Kikuiri T, et al. Expression of receptor acti-vator of NF-kappa B ligand and osteoprotegerin in culture of human pe-riodontal ligament cells[J]. J Periodontal Res, 2002, 37(6): 405-411.
[13] Matsuzak K, Udagawa N, Takahashi N,et al. Osteoclast differentiation factor(ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures[J]. Biochem Biophys Res Commun, 1998, 246: 199-204.
[14] Kong YY, Yoshida, Sarosi T, et al. OPGL is a key regulator or osteoclastogenesis, lymphocyte development and lymph-node organogenesis[J]. Nature, 1999, 397: 315-323.
[15] Romas E, Sims NA, Hards DK, et al. Osteoprotegerin reduces osteoclastnumbers and preventsboneerosionincollagen-induced arthritis[J]. Am J Pathol, 2002, 161(4): 14 19-1427.
[16] Suda T. How is bone formed and resorbed?-molecular mechanisms of bone formation and resorption[J]. Biosho Byori, 2002, 50(3): 267-272.
[17] Hofbauer LC, Khosla S, Dunstan CR, et al. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption[J]. J Bone Miner Res, 2000, 15(1): 2-12.
[18] Teitelbaum SL. Bone resorption by osteoclasts[J]. Science, 2000, 89(5484): 1504-1508.
[19] Liu XH, Kirschenbaum A, Yao S, et al. Interactive effect of interleukin-6 and prostaglandin E2 on osteoclastogenesis via the OPG/RANKL/RANK system[J]. Ann N Y Acad Sci, 2006, 1068: 225-233.
[20] Shevde NK, Bendixen AC, Dienger KM, et al. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression[J]. Proc Natl Acad Sci USA, 2000, 97(14): 7829-7834.
[21] Hamsten A, de Faire U, Walldius G, et al. Plasminogen activator inhibitor in plasma:risk factor for recurrent myocardial infarction[J]. Lancet, 1987, 2(8549): 3-9.
[22]白金柱,王岩,王冉东,等.糖皮质激素性骨质疏松骨保护素表达与骨密度的相关性[J].中国临床康复, 2006, 10(32): 75-77.
[23] Makrygiannakis D, af Klint E, Catrina SB, et al. Intraarticular corticosteroids decrease synovial RANKL expression in inflammatory arthritis[J]. Arthritis Rheum, 2006, 54(5): 1463-1472.
[24] Kanzaki H, Chiba M, Takahashi I, et al. Local OPG genetransfer to periodontal tissue inhibits orthodontic tooth movement[J]. JDentRes, 2004, 83(12): 920-925.
[25] Kanzaki H, Chiba M, AraiK, et al. LocalRANKL gene trans-fer to the periodontal tissue accelerates orthodontic tooth movement[J]. GeneTher, 2006, 13(8): 678-685.
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