TLRs在大鼠骨关节炎软骨中的表达及降钙素干预对其的影响
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摘要
目的:探讨软骨细胞内Toll样受体(Toll-like receptors,TLRs)在骨关节炎(Osteoarthritis,OA)进程中表达的特点,以及受降钙素(Calcitonin,CT)干预后的影响。
方法:将75只SD大鼠随机分为三组,手术组与CT干预组各35只,假手术组5只。对手术组与CT干预组的右膝行前交叉韧带切断加内侧半月板切除术,左膝作为空白对照,不予手术。假手术组的右膝只进入关节腔,不处理交叉韧带和半月板。CT干预组动物于术后第二天始行CT15IU/kg隔日皮下注射。前两组大鼠分别于术后7、10、14、21、28、42及56天处死,每组每次处死5只,假手术组动物于术后56天处死并提取标本。对标本进行大体和组织学切片观察。另用Real-time PCR法对手术组和CT干预组动物双膝关节内的软骨标本分别进行TLR2、TLR3、TLR4表达的检测。
结果:手术组大鼠造模7天后可见组织学变化;10天后大体观察出现软骨面暗淡,失去光泽;28天后可见骨赘形成;56天后见软骨缺损,软骨下骨外露。Mankin评分由7天的1.0分到28天的6.6分发展到56天的12.2分,与假手术组相比有显著差异。与手术组相比在同一时间点上,CT干预组大鼠的滑膜增生较少;软骨损伤较轻;骨赘形成较小;Mankin评分也较低。手术组膝关节的软骨细胞中TLR2的表达早期增高,晚期明显受到抑制;TLR3的表达与病变严重程度呈正相关性;TLR4表达增高,但不随病程发展而变化。降钙素干预后TLR2表达早期受到抑制,28天后开始增高;TLR3的表达早期也受到抑制,但随着病程的进展表达逐渐的升高;TLR4的表达在早期也同样受到了抑制。
结论:采用前交叉韧带切断加内侧半月板切除术可以有效的制作大鼠的OA模型;OA病程中,软骨内有TLRs的表达,TLR2先增高后降低;TLR3与病变严重程度呈正相关性;TLR4高表达但在病程中无明显变化。加用降钙素干预后,尤其是在早期,可明显抑制TLRs的表达,OA的症状也明显改善,在OA早期阶段有一定的治疗作用。
Objective: To study the characteristics of the expression of Toll-like receptors ( TLRs) in chondrocyte in the process of Osteoarthritis(OA), and the effect after the intervention of Calcitonin (CT) .
Methods: 75 SD rats were randomly divided into three groups, of which Surgery group and CT intervened group both consisted 35 rats, while non-surgery group consisted 5. Surgery Group and CT intervened Group were intervened by cutting off the anterior cruciate ligament and the medial meniscus of their right knees, while the left knees as the control samples. For the non-surgery group, we did not deal with the cruciate ligaments and meniscus , but only exposed the knee joint cavity. CT intervened Group were subcutaneous injected with CT 15IU/kg every other day from the second day of the surgery. The rats of CT intervened Group and Surgery Group were executed and the samples were extracted at 7,10,14,21,28,42, and 56 days after the surgery with 5 rats each time. Non-surgery group rats were executed at 56 days after knee joint exposion. Specimen’s general and histological sections were observed. Both sides of the knee cartilage specimens were carried out within the TLR2、TLR3、TLR4 expression detection by Real-time PCR.
Results: The model of Group ACLT+MMx can be seen the histological changes 7 days after surgery; after 10 days the general observation of cartilage surface appears dull; after 28 days the formation of osteophyte were shown; after 56 days the defection of cartilage can be seen with exposion of subchondral bone. It is witnessed the development of Mankin score from 7 days of 1.0 to 28 days to 56 days of 6.6 points to 12.2 points. It were significantly different compared with the non-operated group. The expression of TLR2 of the knee cartilage cells of Group ACLT+MMx increased early and inhibited remarkablely in the later stage. The expression of TLR3 was correlated with the severity of diseases. The expression of TLR4 was high but does not change with the course of OA. After using the intervention of Calcitonin, the early expression of TLR2 was inhibited while 28d later the inhibition stopped and the expression increased. TLR3 expression was curtailed early with no change of the increasing tendency. The expression of TLR4 in early stage was also being inhibited.
Conclusion: The resection of anterior cruciate ligament and medial meniscectomy can effectively produce rat OA model. The expression of TLRs in OA process of chondrocyte, of which TLR2 first increased, then decreased, the trend of expression of TLR3 was correlated with the disease severity. The expression of TLR4 was high but does not change with the course of OA. The expression of TLRs was significantly reduced and the symptoms of OA can significantly improve after using the intervention of Calcitonin, especially in the early stage , which have a certain therapeutic effect on OA.
方法:将75只SD大鼠随机分为三组,手术组与CT干预组各35只,假手术组5只。对手术组与CT干预组的右膝行前交叉韧带切断加内侧半月板切除术,左膝作为空白对照,不予手术。假手术组的右膝只进入关节腔,不处理交叉韧带和半月板。CT干预组动物于术后第二天始行CT15IU/kg隔日皮下注射。前两组大鼠分别于术后7、10、14、21、28、42及56天处死,每组每次处死5只,假手术组动物于术后56天处死并提取标本。对标本进行大体和组织学切片观察。另用Real-time PCR法对手术组和CT干预组动物双膝关节内的软骨标本分别进行TLR2、TLR3、TLR4表达的检测。
结果:手术组大鼠造模7天后可见组织学变化;10天后大体观察出现软骨面暗淡,失去光泽;28天后可见骨赘形成;56天后见软骨缺损,软骨下骨外露。Mankin评分由7天的1.0分到28天的6.6分发展到56天的12.2分,与假手术组相比有显著差异。与手术组相比在同一时间点上,CT干预组大鼠的滑膜增生较少;软骨损伤较轻;骨赘形成较小;Mankin评分也较低。手术组膝关节的软骨细胞中TLR2的表达早期增高,晚期明显受到抑制;TLR3的表达与病变严重程度呈正相关性;TLR4表达增高,但不随病程发展而变化。降钙素干预后TLR2表达早期受到抑制,28天后开始增高;TLR3的表达早期也受到抑制,但随着病程的进展表达逐渐的升高;TLR4的表达在早期也同样受到了抑制。
结论:采用前交叉韧带切断加内侧半月板切除术可以有效的制作大鼠的OA模型;OA病程中,软骨内有TLRs的表达,TLR2先增高后降低;TLR3与病变严重程度呈正相关性;TLR4高表达但在病程中无明显变化。加用降钙素干预后,尤其是在早期,可明显抑制TLRs的表达,OA的症状也明显改善,在OA早期阶段有一定的治疗作用。
Objective: To study the characteristics of the expression of Toll-like receptors ( TLRs) in chondrocyte in the process of Osteoarthritis(OA), and the effect after the intervention of Calcitonin (CT) .
Methods: 75 SD rats were randomly divided into three groups, of which Surgery group and CT intervened group both consisted 35 rats, while non-surgery group consisted 5. Surgery Group and CT intervened Group were intervened by cutting off the anterior cruciate ligament and the medial meniscus of their right knees, while the left knees as the control samples. For the non-surgery group, we did not deal with the cruciate ligaments and meniscus , but only exposed the knee joint cavity. CT intervened Group were subcutaneous injected with CT 15IU/kg every other day from the second day of the surgery. The rats of CT intervened Group and Surgery Group were executed and the samples were extracted at 7,10,14,21,28,42, and 56 days after the surgery with 5 rats each time. Non-surgery group rats were executed at 56 days after knee joint exposion. Specimen’s general and histological sections were observed. Both sides of the knee cartilage specimens were carried out within the TLR2、TLR3、TLR4 expression detection by Real-time PCR.
Results: The model of Group ACLT+MMx can be seen the histological changes 7 days after surgery; after 10 days the general observation of cartilage surface appears dull; after 28 days the formation of osteophyte were shown; after 56 days the defection of cartilage can be seen with exposion of subchondral bone. It is witnessed the development of Mankin score from 7 days of 1.0 to 28 days to 56 days of 6.6 points to 12.2 points. It were significantly different compared with the non-operated group. The expression of TLR2 of the knee cartilage cells of Group ACLT+MMx increased early and inhibited remarkablely in the later stage. The expression of TLR3 was correlated with the severity of diseases. The expression of TLR4 was high but does not change with the course of OA. After using the intervention of Calcitonin, the early expression of TLR2 was inhibited while 28d later the inhibition stopped and the expression increased. TLR3 expression was curtailed early with no change of the increasing tendency. The expression of TLR4 in early stage was also being inhibited.
Conclusion: The resection of anterior cruciate ligament and medial meniscectomy can effectively produce rat OA model. The expression of TLRs in OA process of chondrocyte, of which TLR2 first increased, then decreased, the trend of expression of TLR3 was correlated with the disease severity. The expression of TLR4 was high but does not change with the course of OA. The expression of TLRs was significantly reduced and the symptoms of OA can significantly improve after using the intervention of Calcitonin, especially in the early stage , which have a certain therapeutic effect on OA.
引文
1. Lohmander LS. What can we do about osteoarthritis? Arthritis Res 2000;2: 95-100.
2. Kamekura S, Hoshi K, Shimoaka T, et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 2005;13: 632–641.
3. Mankin HJ, Dorfman H, Lippiello L, et al. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips: II.correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am. 1971;53: 523-537.
4. Laurent G, Ameyea and Marian F,Young. Animal models of osteoarthritis: lessons learned while seeking the‘Holy Grail’. Current Opinion in Rheumatology 2006;18: 537–547.
5.欧云生,安洪.鼠骨关节炎动物模型建立的现状.中国比较医学杂志2004; 14(1): 41-44.
6. Fleming BC, Hulstyn MJ, Oksendahl HL,et al. Ligament injury, reconstruction and osteoarthritis. Current Opinion in Orthopaedics 2005;16: 354-362.
7. Inoue A, Takahashi KA, Arai Y, et al.The therapeutic effects of basic fibroblast growth factor contained in gelatin hydrogel microspheres on experimental osteoarthritis in the rabbit knee. Arthritis Rheum 2006;54: 264-270.
8. DeGroot J, Verzijl N, Wenting-van Wijk MJ, et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 2004;50: 1207–1215.
9. Boyd SK, Muller R, Leonard T, Herzog W. Long-term periarticular bone adaptation in a feline knee injury model for posttraumatic experimental osteoarthritis. Osteoarthritis Cartilage 2005;13: 235–242.
10. Cake MA, Read RA, Appleyard RC, et al. The nitric oxide donor glyceryl trinitrate increases subchondral bone sclerosis and cartilage degeneration following ovine meniscectomy. Osteoarthritis Cartilage 2004;12: 974–981.
1. Karsdal MA,Tanko LB,Riis BJ, et al. Calcitonin is involved in cartilage homeostasis: Is calcitonin a treatment for OA? Osteoarthritis and Cartilage 2006;14: 617-624.
2. Sieling PA,Modlin RL.Toll-like receptors: mammalian‘taste receptors’for a smorgasbord of microbial invaders. Curr Opin Microbiol 2002;5(1):70-75.
3. Zhang Z, Schluesener HJ. Mammalian Toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci 2006;63: 2901-2907.
4. Keqiang Chen,Jian Huang,Wanghua Gong,et al. Toll-like receptors in inflammation, infection and cancer. International Immunopharmacology 2007;(7): 1271–1285.
5. Scanzello CR, et al. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Current Opinion in Rheumatology 2008;20: 565–572.
6. SL Su,CD Tsai, CH Lee, et al. Expression and regulation of Toll-like receptor 2 by IL-1b and fibronectin fragments in human articular chondrocytes. Osteoarthritis and Cartilage 2005;13: 879-886.
7. Brentano F,Schorr O,Gay RE,et a1.RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum 2005;52(9): 2656-2665.
8. Roelofs MF,Wenink MH,Toonen EJ,et a1.The functiona variat(Asp 299 gly)of toll-like receptor 4(TLR4)influences TLR 4-mediated cytokine production in rheumatoid atthrifts.J Rheumatol 2008;35(4):558-561.
9. Abdollahi-Roodsaz S,Joosten LA,Roelofs MF,et a1.Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 2007;56(9):2957-2967.
10. Q Zhang, W Hui, GJ Litherland, ea al. Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis 2008 Nov;67(11): 1633-1641.
11. Sondergaard BC, Olsen AK, Sumer EU, et al. Calcitonin stimulates proteoglycan andcollagen Type II biosynthesis in articular cartilage ex vivo, Osteoarthritis Cartilage 2005;13: Suppl A:142.
12. Chen Y,Shyu JF, Santhanagopal A, et al. The calcitonin receptor stimulates Shc tyrosine phosphorylation and Erk1/2 activation. Involvement of Gi, protein kinase C, and calcium. J Biol Chem 1998;273: 19809–19816.
13. Sondergaard BC, Wulf H, Henriksen K,et al. Calcitonin directly attenuates collagen Type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes, Osteoarthritis Cartilage 2006;14(8): 759-768.
14. Hajjaji H, Williams JM, Devogelaer JP, et al. Treatment with calcitonin prevents the net loss of collagen, hyaluronan and proteoglycan aggregates from cartilage in the early stages of canine experimental osteoarthritis. Osteoarthritis Cartilage 2004;12: 904-911.
15. Bagger YZ, Tanko LB, Alexandersen P, et al. Oral salmon calcitonin induced suppression of urinary collagen type II degradation in postmenopausal women: a new potential treatment of osteoarthritis. Bone 2005;37: 425–430.
1. Zhang Z, Schluesener HJ. Mammalian Toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci 2006; 63: 2901-2907.
2. Barton GM. A calculated response: control of inflammation by the innate immune system. J Clin Invest 2008;118: 413-420
3. Joffre O, Nolte MA, Sporri R, et a1. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol Rev 2009; 227: 234-247.
4. Rakoff-Nahoum S, Medzhitov R. Role of toll-like receptors in tissue repair and tumorigenesis. Biochemistry (Mosc) 2008;73: 555-561.
5. Misch EA, Hawn TR. Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond) 2008;114: 347-360.
6. Medzhitov R,Preston-Hurlbutt P,Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Nature 1997; 388(6640): 394-397.
7. Martin MU, Wesche H. Summary and comparison of the signaling mechanisms of the Toll/interlenkin-1 receptor family.Biochim Biophys Acta 2002; 1592(3): 265-280.
8. Brentano F, Kyburz D, Schorr O, et al. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol 2005;233: 90–96.
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28. Scanzello CR, Plaas A, Crow MK, et al. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Current Opinion in Rheumatology 2008;20: 565–572.
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36. Abdollahi-Roodsaz S, Joosten LA, Koenders MI, et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis.J Clin Invest 2008;118: 205–216.
2. Kamekura S, Hoshi K, Shimoaka T, et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 2005;13: 632–641.
3. Mankin HJ, Dorfman H, Lippiello L, et al. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips: II.correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am. 1971;53: 523-537.
4. Laurent G, Ameyea and Marian F,Young. Animal models of osteoarthritis: lessons learned while seeking the‘Holy Grail’. Current Opinion in Rheumatology 2006;18: 537–547.
5.欧云生,安洪.鼠骨关节炎动物模型建立的现状.中国比较医学杂志2004; 14(1): 41-44.
6. Fleming BC, Hulstyn MJ, Oksendahl HL,et al. Ligament injury, reconstruction and osteoarthritis. Current Opinion in Orthopaedics 2005;16: 354-362.
7. Inoue A, Takahashi KA, Arai Y, et al.The therapeutic effects of basic fibroblast growth factor contained in gelatin hydrogel microspheres on experimental osteoarthritis in the rabbit knee. Arthritis Rheum 2006;54: 264-270.
8. DeGroot J, Verzijl N, Wenting-van Wijk MJ, et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 2004;50: 1207–1215.
9. Boyd SK, Muller R, Leonard T, Herzog W. Long-term periarticular bone adaptation in a feline knee injury model for posttraumatic experimental osteoarthritis. Osteoarthritis Cartilage 2005;13: 235–242.
10. Cake MA, Read RA, Appleyard RC, et al. The nitric oxide donor glyceryl trinitrate increases subchondral bone sclerosis and cartilage degeneration following ovine meniscectomy. Osteoarthritis Cartilage 2004;12: 974–981.
1. Karsdal MA,Tanko LB,Riis BJ, et al. Calcitonin is involved in cartilage homeostasis: Is calcitonin a treatment for OA? Osteoarthritis and Cartilage 2006;14: 617-624.
2. Sieling PA,Modlin RL.Toll-like receptors: mammalian‘taste receptors’for a smorgasbord of microbial invaders. Curr Opin Microbiol 2002;5(1):70-75.
3. Zhang Z, Schluesener HJ. Mammalian Toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci 2006;63: 2901-2907.
4. Keqiang Chen,Jian Huang,Wanghua Gong,et al. Toll-like receptors in inflammation, infection and cancer. International Immunopharmacology 2007;(7): 1271–1285.
5. Scanzello CR, et al. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Current Opinion in Rheumatology 2008;20: 565–572.
6. SL Su,CD Tsai, CH Lee, et al. Expression and regulation of Toll-like receptor 2 by IL-1b and fibronectin fragments in human articular chondrocytes. Osteoarthritis and Cartilage 2005;13: 879-886.
7. Brentano F,Schorr O,Gay RE,et a1.RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum 2005;52(9): 2656-2665.
8. Roelofs MF,Wenink MH,Toonen EJ,et a1.The functiona variat(Asp 299 gly)of toll-like receptor 4(TLR4)influences TLR 4-mediated cytokine production in rheumatoid atthrifts.J Rheumatol 2008;35(4):558-561.
9. Abdollahi-Roodsaz S,Joosten LA,Roelofs MF,et a1.Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 2007;56(9):2957-2967.
10. Q Zhang, W Hui, GJ Litherland, ea al. Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis 2008 Nov;67(11): 1633-1641.
11. Sondergaard BC, Olsen AK, Sumer EU, et al. Calcitonin stimulates proteoglycan andcollagen Type II biosynthesis in articular cartilage ex vivo, Osteoarthritis Cartilage 2005;13: Suppl A:142.
12. Chen Y,Shyu JF, Santhanagopal A, et al. The calcitonin receptor stimulates Shc tyrosine phosphorylation and Erk1/2 activation. Involvement of Gi, protein kinase C, and calcium. J Biol Chem 1998;273: 19809–19816.
13. Sondergaard BC, Wulf H, Henriksen K,et al. Calcitonin directly attenuates collagen Type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes, Osteoarthritis Cartilage 2006;14(8): 759-768.
14. Hajjaji H, Williams JM, Devogelaer JP, et al. Treatment with calcitonin prevents the net loss of collagen, hyaluronan and proteoglycan aggregates from cartilage in the early stages of canine experimental osteoarthritis. Osteoarthritis Cartilage 2004;12: 904-911.
15. Bagger YZ, Tanko LB, Alexandersen P, et al. Oral salmon calcitonin induced suppression of urinary collagen type II degradation in postmenopausal women: a new potential treatment of osteoarthritis. Bone 2005;37: 425–430.
1. Zhang Z, Schluesener HJ. Mammalian Toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci 2006; 63: 2901-2907.
2. Barton GM. A calculated response: control of inflammation by the innate immune system. J Clin Invest 2008;118: 413-420
3. Joffre O, Nolte MA, Sporri R, et a1. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol Rev 2009; 227: 234-247.
4. Rakoff-Nahoum S, Medzhitov R. Role of toll-like receptors in tissue repair and tumorigenesis. Biochemistry (Mosc) 2008;73: 555-561.
5. Misch EA, Hawn TR. Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond) 2008;114: 347-360.
6. Medzhitov R,Preston-Hurlbutt P,Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Nature 1997; 388(6640): 394-397.
7. Martin MU, Wesche H. Summary and comparison of the signaling mechanisms of the Toll/interlenkin-1 receptor family.Biochim Biophys Acta 2002; 1592(3): 265-280.
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