前交叉韧带损伤后关节腔微环境因素对基质金属蛋白酶-2表达的影响
摘要
膝关节前交叉韧带(Anterior cruciate ligament,ACL)损伤是一种较常见的运动性损伤,韧带的撕裂或断裂都会造成膝关节不稳,长期损伤会导致膝关节退行性病变,甚至骨关节炎等并发症。当前临床治疗面临最大的挑战就是ACL修复能力较弱,损伤后不能像内侧副韧带一样能够自身功能性修复。除了ACL组织自身存在的先天遗传性差异外,其损伤后关节腔微环境的变化也可能是调节损伤的ACL修复的关键因素。因此本文着重从ACL损伤后的关节腔微环境入手,探讨导致其自身修复失败的主要原因。
本文的主要工作及结果如下:
1)动物实验探讨ACL损伤后关节腔微环境的变化
利用大鼠ACL瞬时扭转损伤模型发现在ACL损伤后关节液中炎症因子IL-1β、IL-6和TNF-α的表达都显著升高。MMP-2以及整体MMPs家族的活性都随时间依赖性增加。体外组织培养实验发现关节腔内组织都向关节液中释放大量的MMP-2,其中以滑膜组织的作用最为显著。因此我们认为在ACL损伤后也会伴随伤口愈合机制的发生,关节腔内组织尤其滑膜组织以及炎症因子所导致的关节液中大量MMPs的累积可能是ACL损伤后不能修复的一个重要的原因所在。
2)体外实验探讨关节腔微环境因素对MMP-2表达的影响
①机械应力与炎症因子对滑膜成纤维细胞MMP-2活性的影响动物实验发现在ACL损伤后滑膜组织可能是关节液中MMPs的主要调节者,体外实验进一步阐明机械应力与炎症因子是否会诱导滑膜成纤维细胞MMP-2的活性表达,以及力-化学因素在调节MMP-2表达中所起的不同作用。实验结果表明机械应力强度的增加能够显著增强MMP-2的活性表达,炎症因子TNF-α以时间以及剂量依赖形式诱导MMP-2活性的增加,然而IL-1α的作用则不显著。当机械应力与炎症因子共同作用于滑膜成纤维细胞时,则对MMP-2活性的增加有着显著的协同作用。整体MMPs活性检测表明机械应力能够诱导MMPs活性的增加而炎症因子则不能,这也意味着机械应力诱导的MMPs是以酶原形式MMPs为主,而炎症因子诱导的则主要是活化形式MMPs。滑膜组织对机械损伤以及炎症因子非常敏感,并且在调节关节液中MMPs的表达起着至关重要的作用,因此在研究膝关节损伤与修复的过程中滑膜组织是不容忽视的。
②机械应力作用下TNF-α与IL-1β对ACL成纤维细胞MMP-2表达的影响ACL损伤后关节腔内伴随着炎症因子、机械应力以及一些修复因子的复杂的动态变化。损伤的关节腔内组织导致各种炎症因子、细胞因子以及基质金属蛋白酶的累积。因此膝关节损伤后关节液中大量MMPs的累积被认为是ACL修复能力弱的关键因素,然而这些因素对ACL成纤维细胞MMP-2活性影响的具体作用还不明了。因此,为了探讨机械损伤应力与炎症因子对MMP-2表达的共同作用,我们进行体外模拟ACL损伤后的关节腔微环境,来阐明力-化学因素对ACL成纤维细胞MMP-2活性表达的影响。结果表明TNF-α与IL-1β能够以时间以及剂量依赖的形式增加MMP-2的活性,其中以IL-1β的作用最为显著。机械应力与炎症因子共同作用能够进一步增强MMP-2的活性。实验结果阐明机械损伤与炎症因子的共同作用对ACL成纤维细胞MMP-2的活性表达起着重要的调控作用。
③机械应力与低氧对HIF-1α和MMP-2表达的影响
除了炎症反应,在ACL损伤后低氧也是调控关节腔微环境的一个重要因素,然而低氧在ACL损伤后作用的机理还不清楚。因此我们在体外模拟低氧以及机械损伤微环境来探讨ACL成纤维细胞在机械应力损伤后低氧对MMP-2、VEGF、CTGF以及HIF-1α表达的影响。实验结果发现机械应力损伤与低氧分别作用于ACL成纤维细胞时能够增加MMP-2、VEGF、CTGF以及HIF-1α表达,但是当两者共同作用时则能进一步增加MMP-2的表达,而下调VEGF、CTGF以及HIF-1α表达。这一结果说明高表达的MMP-2以及低表达的VEGF、CTGF以及HIF-1α对ACL成纤维细胞不利,影响ACL修复能力。而且ACL损伤导致的低氧微环境也可能是组织退行性病变的一个诱因所在。
3) NF-κB信号通路介导ACL成纤维细胞MMP-2的表达
利用信号通路抑制剂来探讨ACL成纤维细胞损伤后调控MMP-2的表达的主要信号通路。实验结果发现NF-κB信号通路抑制剂(Bay11-70082)能够显著抑制MMP-2的表达,而PD98059 (ERK信号通路抑制剂),SP600125 (JNK信号通路抑制剂)以及SB203850 (p38信号通路抑制剂)则对MMP-2的活性没有显著影响。
综合以上结论我们推测,ACL损伤后关节腔微环境的变化可能是导致其自身修复失败的主要原因,通过抑制MMPs的活性以及改善关节腔微环境有利于损伤的ACL修复。
Injury to the anterior cruciate ligament (ACL) causes knee instability, pain, and may result in progressive degeneration and premature osteoarthritis. An injured ACL does not heal satisfactorily as compared to other joint tissues such as medial collateral ligament (MCL), making it as one of the most challenging and intractable clinical problem today. Apart from these intrinsic differences, microenvironment in knee joint cavity also regulates the ligament’s healing ability. Therefore, in this study, we focus on microenvironment of joint cavity to explore the cause of ACL repair failure. The main experiments and results are as follows:
1) Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture
With a rat ACL rotating injury model, we found that levels of IL-1β, IL-6, and TNF-αwere significantly higher in synovial fluids after ACL injury. MMP-2 activity and global MMP activity in synovial fluids also increased significantly in a time-dependent manner. Ex vivo studies showed that all tissues contributed to the elevation of MMP-2 in synovial fluids especially synovium and the injuried ACL. We concluded that although the regular wound healing mechanism also accurs after ACL injury, accumulation of MMP activity in the synovial fluids, due to all of the intraarticular tissues, may be at least one of the important reasons why an injured ACL cannot be repaired.
2) The effects of microenvironment factors on MMP-2 production
①Differential MMP-2 activity induce by mechanical compression and inflammatory factors in synoviocytes
Synovium may be the major regulator of MMPs in joint cavity after injury, in vitro study to determine whether mechanical injury and inflammatory factors will induce MMP-2 production in synoviocytes. We found mechanical compression increased the MMP-2 production. In addition, TNF-αcan also elevate the activity of MMP-2 in a dose dependent manner, while IL-1αdoes not. However, mixture of these two factors dramatically increased MMP-2 production. In addition, mechanical injury had a strong synergistic effect on MMP-2 production with IL-1α, TNF-αand their mixture. The generic MMP activity assay revealed that mechanical compression increased the generic activity by only , APMA treatment increased the generic activity of MMPs induced by compression but not inflammatory factors, which indicated that compression would induced MMPs in pro-form while inflammatory factors induced MMPs mostly in active-form.
②Combined effects of TNF-αand IL-1βon MMP-2 production in ACL fibroblasts under mechanical stretch
The dynamics between inflammatory factors, mechanical stress and healing factors, in an intra-articular joint, are very complex after injury. Injury to intra-articular tissue (anterior cruciate ligament, ACL, synovium) results in accumulation of various pro-inflammatory factors, cytokines and metallo-proteases. Although the presence of increased amounts of MMPs in the joint fluid after knee injury is considered the key factor for ACL poor healing ability; however, the exact role of collective participants of the joint fluid on MMP-2 activity and production has not been fully studied yet. To investigate the combined effects of mechanical injury and inflammation on induction of MMP-2; we mimicked the microenvironment of joint cavity after ACL injury. The results show that TNF-αand IL-1βelevate the activity of MMP-2 in a dose and time dependent manner. In addition, mechanical stretch further enhances the MMP-2 protein levels with TNF-α, IL-1β, and their mixture. Our results conclude that mechanical injury and inflammatory factors collectively induce increased MMP-2 production in ACL fibroblasts.
③Mechanical stretch and HIF-1αaffects vascular endothelial growth factor (VEGF), and connective tissue growth factor (CTGF) in ACL fibroblasts
Hypoxia plays important role in regulating microenvironment of joint cavity after ACL injury, however, its role in mechanical injury is yet to be examined fully in ACL fibroblasts. In this study, we investigated the influence of hypoxia on matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) and hypoxia inducible factor-1 alpha (HIF-1α) expression in ACL fibroblasts after mechanical injury. The real-time PCR results show that mechanical stretch or hypoxia increases the expression of MMP-2, VEGF, CTGF and HIF-1α; however, the synergistic effects of mechanical stretch and hypoxia increased MMP-2 production but decreased the VEGF, CTGF and HIF-1αexpression. Western blot analysis and ELISA also confirmed these results. Our results demonstrate that increased levels of MMP-2 and decreased levels of HIF-1α, VEGF and CTGF are detrimental to ACL fibroblasts hence affecting their healing ability and may be one of the prime reason’s of tissue degeneration under hypoxia resulted after injury.
3) NF-κB pathway is one of critical pathway of the MMP-2 release in the ACL fibroblasts.
In these studies, the production and underlying signaling pathway for MMP-2 were investigated. Further studies showed that the induced MMP-2 was inhibited by Bay11-7082 (NF-ΚB inhibitor), but was not inhibited by PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB203850 (p38 inhibitor).
In summary, our results suggested that the differentially effect of microenvironmental factors on ACL might alter the balance in tissue healing, which might in turn be responsible for the ACL poor healing ability. We believe that improving the microenvironment and intervention of MMPs production in the joint fluid after knee injury would be very important in the tissue injury/remodeling processes of human knee.
本文的主要工作及结果如下:
1)动物实验探讨ACL损伤后关节腔微环境的变化
利用大鼠ACL瞬时扭转损伤模型发现在ACL损伤后关节液中炎症因子IL-1β、IL-6和TNF-α的表达都显著升高。MMP-2以及整体MMPs家族的活性都随时间依赖性增加。体外组织培养实验发现关节腔内组织都向关节液中释放大量的MMP-2,其中以滑膜组织的作用最为显著。因此我们认为在ACL损伤后也会伴随伤口愈合机制的发生,关节腔内组织尤其滑膜组织以及炎症因子所导致的关节液中大量MMPs的累积可能是ACL损伤后不能修复的一个重要的原因所在。
2)体外实验探讨关节腔微环境因素对MMP-2表达的影响
①机械应力与炎症因子对滑膜成纤维细胞MMP-2活性的影响动物实验发现在ACL损伤后滑膜组织可能是关节液中MMPs的主要调节者,体外实验进一步阐明机械应力与炎症因子是否会诱导滑膜成纤维细胞MMP-2的活性表达,以及力-化学因素在调节MMP-2表达中所起的不同作用。实验结果表明机械应力强度的增加能够显著增强MMP-2的活性表达,炎症因子TNF-α以时间以及剂量依赖形式诱导MMP-2活性的增加,然而IL-1α的作用则不显著。当机械应力与炎症因子共同作用于滑膜成纤维细胞时,则对MMP-2活性的增加有着显著的协同作用。整体MMPs活性检测表明机械应力能够诱导MMPs活性的增加而炎症因子则不能,这也意味着机械应力诱导的MMPs是以酶原形式MMPs为主,而炎症因子诱导的则主要是活化形式MMPs。滑膜组织对机械损伤以及炎症因子非常敏感,并且在调节关节液中MMPs的表达起着至关重要的作用,因此在研究膝关节损伤与修复的过程中滑膜组织是不容忽视的。
②机械应力作用下TNF-α与IL-1β对ACL成纤维细胞MMP-2表达的影响ACL损伤后关节腔内伴随着炎症因子、机械应力以及一些修复因子的复杂的动态变化。损伤的关节腔内组织导致各种炎症因子、细胞因子以及基质金属蛋白酶的累积。因此膝关节损伤后关节液中大量MMPs的累积被认为是ACL修复能力弱的关键因素,然而这些因素对ACL成纤维细胞MMP-2活性影响的具体作用还不明了。因此,为了探讨机械损伤应力与炎症因子对MMP-2表达的共同作用,我们进行体外模拟ACL损伤后的关节腔微环境,来阐明力-化学因素对ACL成纤维细胞MMP-2活性表达的影响。结果表明TNF-α与IL-1β能够以时间以及剂量依赖的形式增加MMP-2的活性,其中以IL-1β的作用最为显著。机械应力与炎症因子共同作用能够进一步增强MMP-2的活性。实验结果阐明机械损伤与炎症因子的共同作用对ACL成纤维细胞MMP-2的活性表达起着重要的调控作用。
③机械应力与低氧对HIF-1α和MMP-2表达的影响
除了炎症反应,在ACL损伤后低氧也是调控关节腔微环境的一个重要因素,然而低氧在ACL损伤后作用的机理还不清楚。因此我们在体外模拟低氧以及机械损伤微环境来探讨ACL成纤维细胞在机械应力损伤后低氧对MMP-2、VEGF、CTGF以及HIF-1α表达的影响。实验结果发现机械应力损伤与低氧分别作用于ACL成纤维细胞时能够增加MMP-2、VEGF、CTGF以及HIF-1α表达,但是当两者共同作用时则能进一步增加MMP-2的表达,而下调VEGF、CTGF以及HIF-1α表达。这一结果说明高表达的MMP-2以及低表达的VEGF、CTGF以及HIF-1α对ACL成纤维细胞不利,影响ACL修复能力。而且ACL损伤导致的低氧微环境也可能是组织退行性病变的一个诱因所在。
3) NF-κB信号通路介导ACL成纤维细胞MMP-2的表达
利用信号通路抑制剂来探讨ACL成纤维细胞损伤后调控MMP-2的表达的主要信号通路。实验结果发现NF-κB信号通路抑制剂(Bay11-70082)能够显著抑制MMP-2的表达,而PD98059 (ERK信号通路抑制剂),SP600125 (JNK信号通路抑制剂)以及SB203850 (p38信号通路抑制剂)则对MMP-2的活性没有显著影响。
综合以上结论我们推测,ACL损伤后关节腔微环境的变化可能是导致其自身修复失败的主要原因,通过抑制MMPs的活性以及改善关节腔微环境有利于损伤的ACL修复。
Injury to the anterior cruciate ligament (ACL) causes knee instability, pain, and may result in progressive degeneration and premature osteoarthritis. An injured ACL does not heal satisfactorily as compared to other joint tissues such as medial collateral ligament (MCL), making it as one of the most challenging and intractable clinical problem today. Apart from these intrinsic differences, microenvironment in knee joint cavity also regulates the ligament’s healing ability. Therefore, in this study, we focus on microenvironment of joint cavity to explore the cause of ACL repair failure. The main experiments and results are as follows:
1) Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture
With a rat ACL rotating injury model, we found that levels of IL-1β, IL-6, and TNF-αwere significantly higher in synovial fluids after ACL injury. MMP-2 activity and global MMP activity in synovial fluids also increased significantly in a time-dependent manner. Ex vivo studies showed that all tissues contributed to the elevation of MMP-2 in synovial fluids especially synovium and the injuried ACL. We concluded that although the regular wound healing mechanism also accurs after ACL injury, accumulation of MMP activity in the synovial fluids, due to all of the intraarticular tissues, may be at least one of the important reasons why an injured ACL cannot be repaired.
2) The effects of microenvironment factors on MMP-2 production
①Differential MMP-2 activity induce by mechanical compression and inflammatory factors in synoviocytes
Synovium may be the major regulator of MMPs in joint cavity after injury, in vitro study to determine whether mechanical injury and inflammatory factors will induce MMP-2 production in synoviocytes. We found mechanical compression increased the MMP-2 production. In addition, TNF-αcan also elevate the activity of MMP-2 in a dose dependent manner, while IL-1αdoes not. However, mixture of these two factors dramatically increased MMP-2 production. In addition, mechanical injury had a strong synergistic effect on MMP-2 production with IL-1α, TNF-αand their mixture. The generic MMP activity assay revealed that mechanical compression increased the generic activity by only , APMA treatment increased the generic activity of MMPs induced by compression but not inflammatory factors, which indicated that compression would induced MMPs in pro-form while inflammatory factors induced MMPs mostly in active-form.
②Combined effects of TNF-αand IL-1βon MMP-2 production in ACL fibroblasts under mechanical stretch
The dynamics between inflammatory factors, mechanical stress and healing factors, in an intra-articular joint, are very complex after injury. Injury to intra-articular tissue (anterior cruciate ligament, ACL, synovium) results in accumulation of various pro-inflammatory factors, cytokines and metallo-proteases. Although the presence of increased amounts of MMPs in the joint fluid after knee injury is considered the key factor for ACL poor healing ability; however, the exact role of collective participants of the joint fluid on MMP-2 activity and production has not been fully studied yet. To investigate the combined effects of mechanical injury and inflammation on induction of MMP-2; we mimicked the microenvironment of joint cavity after ACL injury. The results show that TNF-αand IL-1βelevate the activity of MMP-2 in a dose and time dependent manner. In addition, mechanical stretch further enhances the MMP-2 protein levels with TNF-α, IL-1β, and their mixture. Our results conclude that mechanical injury and inflammatory factors collectively induce increased MMP-2 production in ACL fibroblasts.
③Mechanical stretch and HIF-1αaffects vascular endothelial growth factor (VEGF), and connective tissue growth factor (CTGF) in ACL fibroblasts
Hypoxia plays important role in regulating microenvironment of joint cavity after ACL injury, however, its role in mechanical injury is yet to be examined fully in ACL fibroblasts. In this study, we investigated the influence of hypoxia on matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) and hypoxia inducible factor-1 alpha (HIF-1α) expression in ACL fibroblasts after mechanical injury. The real-time PCR results show that mechanical stretch or hypoxia increases the expression of MMP-2, VEGF, CTGF and HIF-1α; however, the synergistic effects of mechanical stretch and hypoxia increased MMP-2 production but decreased the VEGF, CTGF and HIF-1αexpression. Western blot analysis and ELISA also confirmed these results. Our results demonstrate that increased levels of MMP-2 and decreased levels of HIF-1α, VEGF and CTGF are detrimental to ACL fibroblasts hence affecting their healing ability and may be one of the prime reason’s of tissue degeneration under hypoxia resulted after injury.
3) NF-κB pathway is one of critical pathway of the MMP-2 release in the ACL fibroblasts.
In these studies, the production and underlying signaling pathway for MMP-2 were investigated. Further studies showed that the induced MMP-2 was inhibited by Bay11-7082 (NF-ΚB inhibitor), but was not inhibited by PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB203850 (p38 inhibitor).
In summary, our results suggested that the differentially effect of microenvironmental factors on ACL might alter the balance in tissue healing, which might in turn be responsible for the ACL poor healing ability. We believe that improving the microenvironment and intervention of MMPs production in the joint fluid after knee injury would be very important in the tissue injury/remodeling processes of human knee.
引文
[1] KP Spindler, MM Murray, KB Detwiler, et al. The biomechanical response to doses of TGF-beta 2 in the healing rabbit medial collateral ligament [J]. J Orthop Res,2003,21:245-9.
[2] SL Woo, SS Chan, T Yamaji. Biomechanics of knee ligament healing, repair and reconstruction [J]. J Biomech,1997,30:431-9.
[3] BC Fleming, MJ Hulstyn, HL Oksendahl, et al. Ligament Injury, Reconstruction and Osteoarthritis [J]. Curr Opin Orthop,2005,16:354-62.
[4] CR Allen, GA Livesay, EK Wong, et al. Injury and reconstruction of the anterior cruciate ligament and knee osteoarthritis [J]. Osteoarthritis Cartilage,1999,7:110-21.
[5] E Pennisi. Tending tender tendons [J]. Science,2002,295:1011.
[6] RJ Hawkins, GW Misamore, TR Merritt. Followup of the acute nonoperated isolated anterior cruciate ligament tear [J]. Am J Sports Med,1986,14:205-10.
[7] G Vunjak-Novakovic, G Altman, R Horan, et al. Tissue engineering of ligaments [J]. Annu Rev Biomed Eng,2004,6:131-56.
[8] VS Lin, MC Lee, S O'Neal, et al. Ligament tissue engineering using synthetic biodegradable fiber scaffolds [J]. Tissue Eng,1999,5:443-52.
[9] L Woo, K Hildebrand, N Watanabe, et al. Tissue engineering of ligament and tendon healing [J]. Clin Orthop Relat Res,1999:S312-23.
[10] U Bosch, C Krettek. [Tissue engineering of tendons and ligaments. A new challenge] [J]. Unfallchirurg,2002,105:88-94.
[11] IM Davis, ML Ireland. ACL injuries - The gender bias [J]. J Orthop Sport Phys, 2003,33:A2-A8.
[12] CO Tibesku, J Springer, DS Mastrokalos, et al. Internal rotational strength of the thigh after ACL reconstruction prospective comparison of harvesting of the semitendinosus and gracilis tendons and the patella tendon [J]. Sportverletz Sportsc,2003,17:137-41.
[13] HM Klinger, MH Baums, S Otte, et al. Anterior cruciate reconstruction combined with autologous osteochondral transplantation [J]. Knee Surg Sport Tr A,2003,11:366-71.
[14] Y Barlow, J Willoughby. Pathophysiology of Soft-Tissue Repair [J]. Brit Med Bull,1992,48:698-711.
[15] GM Bokoch, T Katada, JK Northup, et al. Identification of the predominant substrate for ADP-ribosylation by islet activating protein [J]. J Biol Chem,1983,258:2072-5.
[16] J Lee, FL Harwood, WH Akeson, et al. Growth factor expression in healing rabbit medialcollateral and anterior cruciate ligaments [J]. Iowa Orthop J,1998,18:19-25.
[17] MM Murray, KP Spindler, C Devin, et al. Use of a collagen-platelet rich plasma scaffold to stimulate healing of a central defect in the canine ACL [J]. J Orthopaed Res,2006,24:820-30.
[18] M Yoshida, K Fujii. Differences in cellular properties and responses to growth factors between human ACL and MCL cells [J]. J Orthop Sci,1999,4:293-8.
[19] CT Laurencin, JW Freeman. Ligament tissue engineering: an evolutionary materials science approach [J]. Biomaterials,2005,26:7530-6.
[20] D Amiel, C Frank, F Harwood, et al. Tendons and ligaments: a morphological and biochemical comparison [J]. J Orthop Res,1984,1:257-65.
[21] K Riechert, K Labs, K Lindenhayn, et al. Semiquantitative analysis of types I and III collagen from tendons and ligaments in a rabbit model [J]. J Orthop Sci,2001,6:68-74.
[22] SL Woo, PO Newton, DA MacKenna, et al. A comparative evaluation of the mechanical properties of the rabbit medial collateral and anterior cruciate ligaments [J]. J Biomech,1992,25:377-86.
[23]李江,庄逢源,宋国立.膝关节韧带的生物力学研究进展[J].医用生物力学,2005:59-64.
[24] LY Griffin, J Agel, MJ Albohm, et al. Noncontact anterior cruciate ligament injuries: risk factors and prevention strategies [J]. J Am Acad Orthop Surg,2000,8:141-50.
[25] KL Sung, L Yang, DE Whittemore, et al. The differential adhesion forces of anterior cruciate and medial collateral ligament fibroblasts: effects of tropomodulin, talin, vinculin, and alpha-actinin [J]. Proc Natl Acad Sci U S A,1996,93:9182-7.
[26] L Yang, ZY Tang, RY Xue, et al. Proteomics studies on injured ACL and MCL fibroblasts [J]. Biorheology,2008,45:145-6.
[27] L Yang, CM Tsai, AH Hsieh, et al. Adhesion strength differential of human ligament fibroblasts to collagen types I and III [J]. J Orthop Res,1999,17:755-62.
[28] J Witkowski, L Yang, DJ Wood, et al. Migration and healing of ligament cells under inflammatory conditions [J]. J Orthop Res,1997,15:269-77.
[29] MH Geiger, MH Green, A Monosov, et al. An in-Vitro Assay of Anterior Cruciate Ligament (Acl) and Medial Collateral Ligament (Mcl) Cell-Migration [J]. Connective Tissue Research,1994,30:215-24.
[30] CN Nagineni, D Amiel, MH Green, et al. Characterization of the Intrinsic-Properties of the Anterior Cruciate and Medial Collateral Ligament Cells - an Invitro-Cell Culture Study [J]. J Orthopaed Res,1992,10:465-75.
[31] SG Kim, T Akaike, T Sasagawa, et al. Gene expression of type I and type III collagen bymechanical stretch in anterior cruciate ligament cells [J]. Cell Structure and Function, 2002,27:139-44.
[32] ME Wiig, D Amiel, M Ivarsson, et al. Type-I Procollagen Gene-Expression in Normal and Early Healing of the Medial Collateral and Anterior Cruciate Ligaments in Rabbits - an Insitu Hybridization Study [J]. J Orthopaed Res,1991,9:374-82.
[33] T Okuizumi, H Tohyama, E Kondo, et al. The effect of cell-based therapy with autologous synovial fibroblasts activated by exogenous TGF-beta1 on the in situ frozen-thawed anterior cruciate ligament [J]. J Orthop Sci,2004,9:488-94.
[34] K Irie, E Uchiyama, H Iwaso. Intraarticular inflammatory cytokines in acute anterior cruciate ligament injured knee [J]. Knee,2003,10:93-6.
[35] ML Cameron, FH Fu, HH Paessler, et al. Synovial fluid cytokine concentrations as possible prognostic indicators in the ACL-deficient knee [J]. Knee Surg Sports Traumatol Arthrosc,1994,2:38-44.
[36] I Tchetverikov, LS Lohmander, N Verzijl, et al. MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis [J]. Ann Rheum Dis,2005,64:694-8.
[37] P Wang, L Yang, X You, et al. Mechanical stretch regulates the expression of matrix metalloproteinase in rheumatoid arthritis fibroblast-like synoviocytes [J]. Connect Tissue Res,2009,50:98-109.
[38] Y Wang, L Yang, J Zhang, et al. Differential MMP-2 activity induced by mechanical compression and inflammatory factors in human synoviocytes [J]. Mol Cell Biomech,2010,7:105-14.
[39] Z Tang, L Yang, Y Wang, et al. Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture [J]. J Orthop Res,2009,27:243-8.
[40] N Di Girolamo, MJ Verma, PJ McCluskey, et al. Increased matrix metalloproteinases in the aqueous humor of patients and experimental animals with uveitis [J]. Curr Eye Res,1996,15:1060-8.
[41] G Bluteau, J Gouttenoire, T Conrozier, et al. Differential gene expression analysis in a rabbit model of osteoarthritis induced by anterior cruciate ligament (ACL) section [J]. Biorheology,2002,39:247-58.
[42] AB Wysocki, L Staiano-Coico, F Grinnell. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9 [J]. J Invest Dermatol, 1993,101:64-8.
[43] LD Kozaci, DJ Buttle, AP Hollander. Degradation of type II collagen, but not proteoglycan, correlates with matrix metalloproteinase activity in cartilage explant cultures [J]. Arthritis Rheum,1997,40:164-74.
[44] V Everts, E van der Zee, L Creemers, et al. Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling [J]. Histochem J,1996,28:229-45.
[45] B Dai, Y Cao, J Zhou, et al. Abnormal expression of matrix metalloproteinase-2 and -9 in interspecific pregnancy of rat embryos in mouse recipients [J]. Theriogenology, 2003,60:1279-91.
[46] A Talvensaari-Mattila, P Paakko, T Turpeenniemi-Hujanen. Matrix metalloproteinase-2 (MMP-2) is associated with survival in breast carcinoma [J]. Br J Cancer,2003,89:1270-5.
[47] MS Hibbs, JR Hoidal, AH Kang. Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages [J]. J Clin Invest,1987,80:1644-50.
[48] EH Kerkvliet, AJ Docherty, W Beertsen, et al. Collagen breakdown in soft connective tissue explants is associated with the level of active gelatinase A (MMP-2) but not with collagenase [J]. Matrix Biol,1999,18:373-80.
[49] LB Creemers, IDC Jansen, AJP Docherty, et al. Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue [J]. Matrix Biology,1998,17:35-46.
[50] Q Nguyen, G Murphy, PJ Roughley, et al. Degradation of proteoglycan aggregate by a cartilage metalloproteinase. Evidence for the involvement of stromelysin in the generation of link protein heterogeneity in situ [J]. Biochem J,1989,259:61-7.
[51] K Subramaniam, CM Pech, MC Stacey, et al. Induction of MMP-1, MMP-3 and TIMP-1 in normal dermal fibroblasts by chronic venous leg ulcer wound fluid* [J]. Int Wound J,2008,5:79-86.
[52] K Suzuki, JJ Enghild, T Morodomi, et al. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin) [J]. Biochemistry,1990,29:10261-70.
[53] HB Sun, H Yokota. Reduction of cytokine-induced expression and activity of MMP-1 and MMP-13 by mechanical strain in MH7A rheumatoid synovial cells [J]. Matrix Biol,2002,21:263-70.
[54] P Patwari, J Fay, MN Cook, et al. In vitro models for investigation of the effects of acute mechanical injury on cartilage [J]. Clin Orthop Relat Res,2001:S61-71.
[55] C Yang, M Zeisberg, B Mosterman, et al. Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors [J]. Gastroenterology,2003,124:147-59.
[56] YL He, EJ Macarak, JM Korostoff, et al. Compression and tension: Differential effects on matrix accumulation by periodontal ligament fibroblasts in vitro [J]. Connective Tissue Research,2004,45:28-39.
[57] JM Archambault, MK Elfervig-Wall, M Tsuzaki, et al. Rabbit tendon cells produce MMP-3 in response to fluid flow without significant calcium transients [J]. Journal of Biomechanics,2002,35:303-9.
[58] AH Hsieh, JC Lotz. Prolonged spinal loading induces matrix metalloproteinase-2 activation in intervertebral discs [J]. Spine,2003,28:1781-8.
[59] D Zhou, HS Lee, F Villarreal, et al. Differential MMP-2 activity of ligament cells under mechanical stretch injury: an in vitro study on human ACL and MCL fibroblasts [J]. J Orthop Res,2005,23:949-57.
[60] H Louboutin, R Debarge, J Richou, et al. Osteoarthritis in patients with anterior cruciate ligament rupture: A review of risk factors [J]. Knee,2009,16:239-44.
[61] BE Oiestad, L Engebretsen, K Storheim, et al. Knee Osteoarthritis After Anterior Cruciate Ligament Injury A Systematic Review [J]. Am J Sport Med,2009,37:1434-43.
[62] F Heraud, A Heraud, MF Harmand. Apoptosis in normal and osteoarthritic human articular cartilage [J]. Annals of the Rheumatic Diseases,2000,59:959-65.
[63] T Aigner, A Hemmel, D Neureiter, et al. Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritic human articular knee cartilage - A study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage [J]. Arthritis and Rheumatism,2001,44:1304-12.
[64] GL Semenza, GL Wang. A Nuclear Factor Induced by Hypoxia Via Denovo Protein-Synthesis Binds to the Human Erythropoietin Gene Enhancer at a Site Required for Transcriptional Activation [J]. Molecular and Cellular Biology,1992,12:5447-54.
[65]戴辰程.缺氧诱导因子-1与类风湿关节炎[J].国外医学(免疫学分册),2005:298-302.
[66] NV Iyer, SW Leung, GL Semenza. The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation [J]. Genomics,1998,52:159-65.
[67] GL Semenza. Targeting HIF-1 for cancer therapy [J]. Nat Rev Cancer,2003,3:721-32.
[68] NA Whitlock, N Agarwal, JX Ma, et al. Hsp27 upregulation by HIF-1 signaling offers protection against retinal ischemia in rats [J]. Invest Ophthalmol Vis Sci,2005,46:1092-8.
[69] GL Semenza. HIF-1: mediator of physiological and pathophysiological responses to hypoxia [J]. J Appl Physiol,2000,88:1474-80.
[70] A Weidemann, WM Bernhardt, B Klanke, et al. HIF activation protects from acute kidneyinjury [J]. Journal of the American Society of Nephrology,2008,19:486-94.
[71] RK Bruick, SL McKnight. Transcription - Oxygen sensing gets a second wind [J]. Science,2002,295:807-8.
[72] IR Botusan, VG Sunkari, O Savu, et al. Stabilization of HIF-1 alpha is critical to improve wound healing in diabetic mice [J]. P Natl Acad Sci USA,2008,105:19426-31.
[73] JX Chen, T Zhao, DX Huang. Protective effects of edaravone against cobalt chloride-induced apoptosis in PC12 cells [J]. Neurosci Bull,2009,25:67-74.
[74] GH Altman, HH Lu, RL Horan, et al. Advanced bioreactor with controlled application of multi-dimensional strain for tissue engineering [J]. J Biomech Eng,2002,124:742-9.
[75] J Garvin, J Qi, M Maloney, et al. Novel system for engineering bioartificial tendons and application of mechanical load [J]. Tissue Eng,2003,9:967-79.
[76] G Matziolis, J Tuischer, G Kasper, et al. Simulation of cell differentiation in fracture healing: Mechanically loaded composite scaffolds in a novel bioreactor system [J]. Tissue Engineering,2006,12:201-8.
[77] FG Giancotti. Integrin signaling: specificity and control of cell survival and cell cycle progression [J]. Curr Opin Cell Biol,1997,9:691-700.
[78] KL Sung, DE Whittemore, L Yang, et al. Signal pathways and ligament cell adhesiveness [J]. J Orthop Res,1996,14:729-35.
[79] SP Arnoczky, T Tian, M Lavagnino, et al. Activation of stress-activated protein kinases (SAPK) in tendon cells following cyclic strain: the effects of strain frequency, strain magnitude, and cytosolic calcium [J]. J Orthopaed Res,2002,20:947-52.
[80] SA Park, IA Kim, YJ Lee, et al. Biological responses of ligament fibroblasts and gene expression profiling on micropatterned silicone substrates subjected to mechanical stimuli [J]. J Biosci Bioeng,2006,102:402-12.
[81] J Zeichen, M van Griensven, U Bosch. The proliferative response of isolated human tendon fibroblasts to cyclic biaxial mechanical strain [J]. Am J Sports Med,2000,28:888-92.
[82] G Yang, RC Crawford, JH Wang. Proliferation and collagen production of human patellar tendon fibroblasts in response to cyclic uniaxial stretching in serum-free conditions [J]. J Biomech,2004,37:1543-50.
[83] CH Lee, HJ Shin, IH Cho, et al. Nanofiber alignment and direction of mechanical strain affect the ECM production of human ACL fibroblast [J]. Biomaterials,2005,26:1261-70.
[84] T Toyoda, H Matsumoto, K Fujikawa, et al. Tensile load and the metabolism of anterior cruciate ligament cells [J]. Clin Orthop Relat Res,1998:247-55.
[85] JA Hannafin, SP Arnoczky, A Hoonjan, et al. Effect of stress deprivation and cyclic tensileloading on the material and morphologic properties of canine flexor digitorum profundus tendon: an in vitro study [J]. J Orthop Res,1995,13:907-14.
[86] N Yamamoto, K Ohno, K Hayashi, et al. Effects of stress shielding on the mechanical properties of rabbit patellar tendon [J]. J Biomech Eng,1993,115:23-8.
[87] RC Buck. Reorientation response of cells to repeated stretch and recoil of the substratum [J]. Exp Cell Res,1980,127:470-4.
[88] C Neidlinger-Wilke, E Grood, L Claes, et al. Fibroblast orientation to stretch begins within three hours [J]. J Orthop Res,2002,20:953-6.
[89] C Neidlinger-Wilke, ES Grood, JHC Wang, et al. Cell alignment is induced by cyclic changes in cell length: studies of cells grown in cyclically stretched substrates [J]. J Orthopaed Res,2001,19:286-93.
[90] TW Gilbert, AM Stewart-Akers, J Sydeski, et al. Gene expression by fibroblasts seeded on small intestinal submucosa and subjected to cyclic stretching [J]. Tissue Engineering, 2007,13:1313-23.
[91] JHC Wang, GG Yang, ZZ Li, et al. Fibroblast responses to cyclic mechanical stretching depend on cell orientation to the stretching direction [J]. Journal of Biomechanics, 2004,37:573-6.
[92] JHC Wang, FY Jia, TW Gilbert, et al. Cell orientation determines the alignment of cell-produced collagenous matrix [J]. Journal of Biomechanics,2003,36:97-102.
[93] MS Jones, AJ Banes, ME Wall, et al. Ligament cells stretched on a microgrooved substrate increase intracellular calcium in response to a mechanical stimulus [J]. Mater Res Soc Symp P,2004,1:197-9.
[94] BF Jones, ME Wall, RL Carroll, et al. Ligament cells stretch-adapted on a microgrooved substrate increase intercellular communication in response to a mechanical stimulus [J]. Journal of Biomechanics,2005,38:1653-64.
[95] M Chiquet. Regulation of extracellular matrix gene expression by mechanical stress [J]. Matrix Biology,1999,18:417-26.
[96] AH Hsieh, CMH Tsai, QJ Ma, et al. Time-dependent increases in type-III collagen gene expression in medial collateral ligament fibroblasts under cyclic strains [J]. J Orthopaed Res,2000,18:220-7.
[97] CY Lee, XH Liu, CL Smith, et al. The combined regulation of estrogen and cyclic tension on fibroblast biosynthesis derived from anterior cruciate ligament [J]. Matrix Biology,2004,23:323-9.
[98] T Marui, C Niyibizi, HI Georgescu, et al. Effect of growth factors on matrix synthesis byligament fibroblasts [J]. J Orthopaed Res,1997,15:18-23.
[99] M Skutek, M van Griensven, J Zeichen, et al. Cyclic mechanical stretching modulates secretion pattern of growth factors in human tendon fibroblasts [J]. European Journal of Applied Physiology,2001,86:48-52.
[100] D Amiel, WH Akeson, FL Harwood, et al. Stress Deprivation Effect on Metabolic Turnover of the Medial Collateral Ligament Collagen - a Comparison between 9-Week and 12-Week Immobilization [J]. Clin Orthop Relat R,1983:265-70.
[101] WH Akeson, D Amiel, MF Abel, et al. Effects of Immobilization on Joints [J]. Clin Orthop Relat R,1987:28-37.
[102] D Amiel, SLY Woo, FL Harwood, et al. The Effect of Immobilization on Collagen Turnover in Connective-Tissue - a Biochemical-Biomechanical Correlation [J]. Acta Orthopaedica Scandinavica,1982,53:325-32.
[103] K Hayashi. Biomechanical studies of the remodeling of knee joint tendons and ligaments [J]. Journal of Biomechanics,1996,29:707-16.
[104] K Yasuda, K Hayashi. Changes in biomechanical properties of tendons and ligaments from joint disuse [J]. Osteoarthr Cartilage,1999,7:122-9.
[105] FP Barry. Biology and clinical applications of mesenchymal stem cells [J]. Birth Defects Res C Embryo Today,2003,69:250-6.
[106] U Noth, K Schupp, A Heymer, et al. Anterior cruciate ligament constructs fabricated from human mesenchymal stem cells in a collagen type I hydrogel [J]. Cytotherapy, 2005,7:447-55.
[107] J Chen, RL Horan, D Bramono, et al. Monitoring mesenchymal stromal cell developmental stage to apply on-time mechanical stimulation for ligament tissue engineering [J]. Tissue Eng,2006,12:3085-95.
[108] GH Altman, RL Horan, I Martin, et al. Cell differentiation by mechanical stress [J]. FASEB J,2002,16:270-2.
[109] IC Lee, JH Wang, YT Lee, et al. The differentiation of mesenchymal stem cells by mechanical stress or/and co-culture system [J]. Biochem Bioph Res Co,2007,352:147-52.
[110] N Juncosa-Melvin, JT Shearn, GP Boivin, et al. Effects of mechanical stimulation on the biomechanics and histology of stem cell-collagen sponge constructs for rabbit patellar tendon repair [J]. Tissue Engineering,2006,12:2291-300.
[111] CF Ettlinger, RJ Johnson, JE Shealy. A Method to Help Reduce the Risk of Serious Knee Sprains Incurred in Alpine Skiing [J]. Am J Sport Med,1995,23:531-7.
[112] FR Noyes, PA Mooar, DS Matthews, et al. The Symptomatic Anterior Cruciate-DeficientKnee .1. The Long-Term Functional Disability in Athletically Active Individuals [J]. Journal of Bone and Joint Surgery-American Volume,1983,65:154-62.
[113] FR Noyes, DS Matthews, PA Mooar, et al. The Symptomatic Anterior Cruciate-Deficient Knee .2. The Results of Rehabilitation, Activity Modification, and Counseling on Functional Disability [J]. Journal of Bone and Joint Surgery-American Volume,1983,65:163-74.
[114] DA Bettinger, JV Pellicane, WC Tarry, et al. The Role of Inflammatory Cytokines in Wound-Healing - Accelerated Healing in Endotoxin-Resistant Mice [J]. Journal of Trauma-Injury Infection and Critical Care,1994,36:810-3.
[115] CA Dinarello. The Interleukin-1 Family - 10 Years of Discovery [J]. Faseb Journal,1994,8:1314-25.
[116] DP Mooney, M Oreilly, RL Gamelli. Tumor Necrosis Factor and Wound-Healing [J]. Annals of Surgery,1990,211:124-9.
[117] NG Frangogiannis, CW Smith, ML Entman. The inflammatory response in myocardial infarction [J]. Cardiovascular Research,2002,53:31-47.
[118] FC Iwuagwu, DA McGrouther. Early cellular response in tendon injury: The effect of loading [J]. Plastic and Reconstructive Surgery,1998,102:2064-71.
[119] D Marsolais, CH Cote, J Frenette. Neutrophils and macrophages accumulate sequentially following Achilles tendon injury [J]. J Orthop Res,2001,19:1203-9.
[120] RB Mateo, JS Reichner, JE Albina. Interleukin-6 activity in wounds [J]. Am J Physiol,1994,266:R1840-4.
[121] RM Gallucci, PP Simeonova, JM Matheson, et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice [J]. FASEB J,2000,14:2525-31.
[122] RG Holzheimer, W Steinmetz. Local and systemic concentrations of pro- and anti-inflammatory cytokines in human wounds [J]. Eur J Med Res,2000,5:347-55.
[123] MS Agren. Gelatinase activity during wound healing [J]. Br J Dermatol,1994,131:634-40.
[124] H Nagase, R Visse, G Murphy. Structure and function of matrix metalloproteinases and TIMPs [J]. Cardiovasc Res,2006,69:562-73.
[125] R Visse, H Nagase. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry [J]. Circ Res,2003,92:827-39.
[126] MJ Foos, JR Hickox, PG Mansour, et al. Expression of matrix metalloprotease and tissue inhibitor of metalloprotease genes in human anterior cruciate ligament [J]. J Orthop Res,2001,19:642-9.
[127] AB Wysocki, L Staianocoico, F Grinnell. Wound Fluid from Chronic Leg Ulcers Contains Elevated Levels of Metalloproteinases Mmp-2 and Mmp-9 [J]. Journal of InvestigativeDermatology,1993,101:64-8.
[128] E Louis, KA Remer, MG Doherr, et al. Nitric oxide and metalloproteinases in canine articular ligaments: a comparison between the cranial cruciate, the medial genual collateral and the femoral head ligament [J]. Vet J,2006,172:466-72.
[129] P Muir, PA Manley, Z Hao. Collagen fragmentation in ruptured canine cranial cruciate ligament explants [J]. Vet J,2006,172:121-8.
[130] MPH Le Graverand, J Eggerer, P Sciore, et al. Matrix metalloproteinase-13 expression in rabbit knee joint connective tissues: influence of maturation and response to injury [J]. Matrix Biology,2000,19:431-41.
[131] GS Firestein. Evolving concepts of rheumatoid arthritis [J]. Nature,2003,423:356-61.
[132] T Pap, WH van der Laan, KR Aupperle, et al. Modulation of fibroblast-mediated cartilage degradation by articular chondrocytes in rheumatoid arthritis [J]. Arthritis Rheum,2000,43:2531-6.
[133] F De Benedetti, P Pignatti, V Gerloni, et al. Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis [J]. J Rheumatol,1997,24:1403-9.
[134] JHW Distler, A Jungel, LC Huber, et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles [J]. P Natl Acad Sci USA,2005,102:2892-7.
[135] TN Trumble, GW Trotter, JR Oxford, et al. Synovial fluid gelatinase concentrations and matrix metalloproteinase and cytokine expression in naturally occurring joint disease in horses [J]. Am J Vet Res,2001,62:1467-77.
[136] EJ Barone, DR Yager, AL Pozez, et al. Interleukin-1alpha and collagenase activity are elevated in chronic wounds [J]. Plast Reconstr Surg,1998,102:1023-7; discussion 8-9.
[137] F Quatra, MR Colonna, A Catalano. The role of interleukin-1alpha and collagenase in chronic wounds [J]. Plast Reconstr Surg,1999,104:1205-6.
[138] TS Momberger, JR Levick, RM Mason. Hyaluronan secretion by synoviocytes is mechanosensitive [J]. Matrix Biology,2005,24:510-9.
[139] Z Tang, L Yang, R Xue, et al. Differential expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in anterior cruciate ligament and medial collateral ligament fibroblasts after a mechanical injury: involvement of the p65 subunit of NF-kappaB [J]. Wound Repair Regen,2009,17:709-16.
[140] AA Lee, T Delhaas, LK Waldman, et al. An equibiaxial strain system for cultured cells [J]. Am J Physiol,1996,271:C1400-8.
[141] AA Lee, T Delhaas, AD McCulloch, et al. Differential responses of adult cardiac fibroblaststo in vitro biaxial strain patterns [J]. J Mol Cell Cardiol,1999,31:1833-43.
[142] J Zhang, L Yang, Z Tang, et al. Expression of MMPs and TIMPs Family in Human ACL and MCL Fibroblasts [J]. Connective Tissue Research,2009,50:7-13.
[143] M Tsuzaki, G Guyton, W Garrett, et al. IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells [J]. J Orthop Res,2003,21:256-64.
[144] W Petersen, B Tillmann. Structure and vascularization of the cruciate ligaments of the human knee joint [J]. Anat Embryol (Berl),1999,200:325-34.
[145] TD Warner, JA Mitchell. HIF, stretching to get control of VEGF [J]. Clin Sci (Lond),2003,105:393-4.
[146] KH Hong, SA Yoo, SS Kang, et al. Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts [J]. Clin Exp Immunol,2006,146:362-70.
[147] W Petersen, D Varoga, T Zantop, et al. Cyclic strain influences the expression of the vascular endothelial growth factor (VEGF) and the hypoxia inducible factor 1 alpha (HIF-1 alpha) in tendon fibroblasts [J]. J Orthopaed Res,2004,22:847-53.
[148] AA Tandara, TA Mustoe. Oxygen in wound healing--more than a nutrient [J]. World J Surg,2004,28:294-300.
[149] H Kofoed. Synovitis causes hypoxia and acidity in synovial fluid and subchondral bone [J]. Injury,1986,17:391-4.
[150] HS Cha, KS Ahn, CH Jeon, et al. Influence of hypoxia on the expression of matrix metalloproteinase-1, -3 and tissue inhibitor of metalloproteinase-1 in rheumatoid synovial fibroblasts [J]. Clin Exp Rheumatol,2003,21:593-8.
[151] EA Ayello, JE Cuddigan. Conquer chronic wounds with wound bed preparation [J]. Nurse Pract,2004,29:8-25; quiz 6-7.
[152] GM Gordillo, CK Sen. Revisiting the essential role of oxygen in wound healing [J]. American Journal of Surgery,2003,186:259-63.
[153] Z Wood. Hyperbaric oxygen in the management of chronic wounds [J]. Br J Nurs,2002,11:S16, S8-9, S22-4.
[154] JA Thackham, DLS McElwain, RJ Long. The use of hyperbaric oxygen therapy to treat chronic wounds: A review [J]. Wound Repair and Regeneration,2008,16:321-30.
[155] TD Ardyanto, M Osaki, N Tokuyasu, et al. CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway [J]. Int J Oncol,2006,29:549-55.
[156] F Heraud, A Heraud, MF Harmand. Apoptosis in normal and osteoarthritic human articular cartilage [J]. Ann Rheum Dis,2000,59:959-65.
[157] T Aigner, M Hemmel, D Neureiter, et al. Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage [J]. Arthritis Rheum,2001,44:1304-12.
[158]韩建群,余明华,戴旻, et al.氯化钴化学模拟低氧对肿瘤细胞增殖及凋亡的影响[J].基础医学与临床,2008:867-72.
[159] D Amiel, E Billings, Jr., FL Harwood. Collagenase activity in anterior cruciate ligament: protective role of the synovial sheath [J]. J Appl Physiol,1990,69:902-6.
[160] EC Finger, AJ Giaccia. Hypoxia, inflammation, and the tumor microenvironment in metastatic disease [J]. Cancer Metastasis Rev,2010,29:285-93.
[161] S Kondo, S Kubota, T Shimo, et al. Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases [J]. Carcinogenesis,2002,23:769-76.
[162] RF Diegelmann, MC Evans. Wound healing: An overview of acute, fibrotic and delayed healing [J]. Frontiers in Bioscience,2004,9:283-9.
[163] AB Wysocki, AO Kusakabe, S Chang, et al. Temporal expression of matrix metalloproteinase-9 and urokinase plasminogen activator in human chronic wound fluids. [J]. Molecular Biology of the Cell,1998,9:420a-a.
[164] AB Wysocki, AO Kusakabe, S Chang, et al. Temporal expression of urokinase plasminogen activator, plasminogen activator inhibitor and gelatinase-B in chronic wound fluid switches from a chronic to acute wound profile with progression to healing [J]. Wound Repair and Regeneration,1999,7:154-65.
[165] J Westermarck, VM Kahari. Regulation of matrix metalloproteinase expression in turner invasion [J]. Faseb Journal,1999,13:781-92.
[166] H Nagase, JF Woessner, Jr. Matrix metalloproteinases [J]. J Biol Chem,1999,274:21491-4.
[167] M Karin, Z Liu, E Zandi. AP-1 function and regulation [J]. Curr Opin Cell Biol,1997,9:240-6.
[168] X Wang, T Mori, JC Jung, et al. Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase [J]. J Neurotrauma,2002,19:615-25.
[169] JHC Wang, BP Thampatty, JS Lin, et al. Mechanoregulation of gene expression in fibroblasts [J]. Gene,2007,391:1-15.
[170] Z Han, DL Boyle, AM Manning, et al. AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen-induced arthritis [J]. Autoimmunity,1998,28:197-208.
[171] X Dolcet, D Llobet, J Pallares, et al. NF-kB in development and progression of human cancer [J]. Virchows Archiv,2005,446:475-82.
[172] HK Eltzschig, P Carmeliet. Mechanisms of Disease: Hypoxia and Inflammation. [J]. New Engl J Med,2011,364:656-65.
[173] HK Eltzschig. Targeting Hypoxia-induced Inflammation [J]. Anesthesiology, 2011, 114:239-42.
[174] P Wang, X You, Y Yan, et al. Cyclic mechanical stretch downregulates IL-1 beta-induced COX-2 expression and PGE(2) production in rheumatoid arthritis fibroblast-like synoviocytes [J]. Connective Tissue Research,2011,52:190-7.
[175] JH Wang, BP Thampatty, JS Lin, et al. Mechanoregulation of gene expression in fibroblasts [J]. Gene,2007,391:1-15.
[176] Y Wang, Z Tang, R Xue, et al. TGF-beta1 promoted MMP-2 mediated wound healing of anterior cruciate ligament fibroblasts through NF-kappaB [J]. Connect Tissue Res,2011,52:218-25.
[177] F Mannello. Serum or plasma samples? The "Cinderella" role of blood collection procedures: preanalytical methodological issues influence the release and activity of circulating matrix metalloproteinases and their tissue inhibitors, hampering diagnostic trueness and leading to misinterpretation [J]. Arterioscler Thromb Vasc Biol,2008,28:611-4.
[2] SL Woo, SS Chan, T Yamaji. Biomechanics of knee ligament healing, repair and reconstruction [J]. J Biomech,1997,30:431-9.
[3] BC Fleming, MJ Hulstyn, HL Oksendahl, et al. Ligament Injury, Reconstruction and Osteoarthritis [J]. Curr Opin Orthop,2005,16:354-62.
[4] CR Allen, GA Livesay, EK Wong, et al. Injury and reconstruction of the anterior cruciate ligament and knee osteoarthritis [J]. Osteoarthritis Cartilage,1999,7:110-21.
[5] E Pennisi. Tending tender tendons [J]. Science,2002,295:1011.
[6] RJ Hawkins, GW Misamore, TR Merritt. Followup of the acute nonoperated isolated anterior cruciate ligament tear [J]. Am J Sports Med,1986,14:205-10.
[7] G Vunjak-Novakovic, G Altman, R Horan, et al. Tissue engineering of ligaments [J]. Annu Rev Biomed Eng,2004,6:131-56.
[8] VS Lin, MC Lee, S O'Neal, et al. Ligament tissue engineering using synthetic biodegradable fiber scaffolds [J]. Tissue Eng,1999,5:443-52.
[9] L Woo, K Hildebrand, N Watanabe, et al. Tissue engineering of ligament and tendon healing [J]. Clin Orthop Relat Res,1999:S312-23.
[10] U Bosch, C Krettek. [Tissue engineering of tendons and ligaments. A new challenge] [J]. Unfallchirurg,2002,105:88-94.
[11] IM Davis, ML Ireland. ACL injuries - The gender bias [J]. J Orthop Sport Phys, 2003,33:A2-A8.
[12] CO Tibesku, J Springer, DS Mastrokalos, et al. Internal rotational strength of the thigh after ACL reconstruction prospective comparison of harvesting of the semitendinosus and gracilis tendons and the patella tendon [J]. Sportverletz Sportsc,2003,17:137-41.
[13] HM Klinger, MH Baums, S Otte, et al. Anterior cruciate reconstruction combined with autologous osteochondral transplantation [J]. Knee Surg Sport Tr A,2003,11:366-71.
[14] Y Barlow, J Willoughby. Pathophysiology of Soft-Tissue Repair [J]. Brit Med Bull,1992,48:698-711.
[15] GM Bokoch, T Katada, JK Northup, et al. Identification of the predominant substrate for ADP-ribosylation by islet activating protein [J]. J Biol Chem,1983,258:2072-5.
[16] J Lee, FL Harwood, WH Akeson, et al. Growth factor expression in healing rabbit medialcollateral and anterior cruciate ligaments [J]. Iowa Orthop J,1998,18:19-25.
[17] MM Murray, KP Spindler, C Devin, et al. Use of a collagen-platelet rich plasma scaffold to stimulate healing of a central defect in the canine ACL [J]. J Orthopaed Res,2006,24:820-30.
[18] M Yoshida, K Fujii. Differences in cellular properties and responses to growth factors between human ACL and MCL cells [J]. J Orthop Sci,1999,4:293-8.
[19] CT Laurencin, JW Freeman. Ligament tissue engineering: an evolutionary materials science approach [J]. Biomaterials,2005,26:7530-6.
[20] D Amiel, C Frank, F Harwood, et al. Tendons and ligaments: a morphological and biochemical comparison [J]. J Orthop Res,1984,1:257-65.
[21] K Riechert, K Labs, K Lindenhayn, et al. Semiquantitative analysis of types I and III collagen from tendons and ligaments in a rabbit model [J]. J Orthop Sci,2001,6:68-74.
[22] SL Woo, PO Newton, DA MacKenna, et al. A comparative evaluation of the mechanical properties of the rabbit medial collateral and anterior cruciate ligaments [J]. J Biomech,1992,25:377-86.
[23]李江,庄逢源,宋国立.膝关节韧带的生物力学研究进展[J].医用生物力学,2005:59-64.
[24] LY Griffin, J Agel, MJ Albohm, et al. Noncontact anterior cruciate ligament injuries: risk factors and prevention strategies [J]. J Am Acad Orthop Surg,2000,8:141-50.
[25] KL Sung, L Yang, DE Whittemore, et al. The differential adhesion forces of anterior cruciate and medial collateral ligament fibroblasts: effects of tropomodulin, talin, vinculin, and alpha-actinin [J]. Proc Natl Acad Sci U S A,1996,93:9182-7.
[26] L Yang, ZY Tang, RY Xue, et al. Proteomics studies on injured ACL and MCL fibroblasts [J]. Biorheology,2008,45:145-6.
[27] L Yang, CM Tsai, AH Hsieh, et al. Adhesion strength differential of human ligament fibroblasts to collagen types I and III [J]. J Orthop Res,1999,17:755-62.
[28] J Witkowski, L Yang, DJ Wood, et al. Migration and healing of ligament cells under inflammatory conditions [J]. J Orthop Res,1997,15:269-77.
[29] MH Geiger, MH Green, A Monosov, et al. An in-Vitro Assay of Anterior Cruciate Ligament (Acl) and Medial Collateral Ligament (Mcl) Cell-Migration [J]. Connective Tissue Research,1994,30:215-24.
[30] CN Nagineni, D Amiel, MH Green, et al. Characterization of the Intrinsic-Properties of the Anterior Cruciate and Medial Collateral Ligament Cells - an Invitro-Cell Culture Study [J]. J Orthopaed Res,1992,10:465-75.
[31] SG Kim, T Akaike, T Sasagawa, et al. Gene expression of type I and type III collagen bymechanical stretch in anterior cruciate ligament cells [J]. Cell Structure and Function, 2002,27:139-44.
[32] ME Wiig, D Amiel, M Ivarsson, et al. Type-I Procollagen Gene-Expression in Normal and Early Healing of the Medial Collateral and Anterior Cruciate Ligaments in Rabbits - an Insitu Hybridization Study [J]. J Orthopaed Res,1991,9:374-82.
[33] T Okuizumi, H Tohyama, E Kondo, et al. The effect of cell-based therapy with autologous synovial fibroblasts activated by exogenous TGF-beta1 on the in situ frozen-thawed anterior cruciate ligament [J]. J Orthop Sci,2004,9:488-94.
[34] K Irie, E Uchiyama, H Iwaso. Intraarticular inflammatory cytokines in acute anterior cruciate ligament injured knee [J]. Knee,2003,10:93-6.
[35] ML Cameron, FH Fu, HH Paessler, et al. Synovial fluid cytokine concentrations as possible prognostic indicators in the ACL-deficient knee [J]. Knee Surg Sports Traumatol Arthrosc,1994,2:38-44.
[36] I Tchetverikov, LS Lohmander, N Verzijl, et al. MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis [J]. Ann Rheum Dis,2005,64:694-8.
[37] P Wang, L Yang, X You, et al. Mechanical stretch regulates the expression of matrix metalloproteinase in rheumatoid arthritis fibroblast-like synoviocytes [J]. Connect Tissue Res,2009,50:98-109.
[38] Y Wang, L Yang, J Zhang, et al. Differential MMP-2 activity induced by mechanical compression and inflammatory factors in human synoviocytes [J]. Mol Cell Biomech,2010,7:105-14.
[39] Z Tang, L Yang, Y Wang, et al. Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture [J]. J Orthop Res,2009,27:243-8.
[40] N Di Girolamo, MJ Verma, PJ McCluskey, et al. Increased matrix metalloproteinases in the aqueous humor of patients and experimental animals with uveitis [J]. Curr Eye Res,1996,15:1060-8.
[41] G Bluteau, J Gouttenoire, T Conrozier, et al. Differential gene expression analysis in a rabbit model of osteoarthritis induced by anterior cruciate ligament (ACL) section [J]. Biorheology,2002,39:247-58.
[42] AB Wysocki, L Staiano-Coico, F Grinnell. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9 [J]. J Invest Dermatol, 1993,101:64-8.
[43] LD Kozaci, DJ Buttle, AP Hollander. Degradation of type II collagen, but not proteoglycan, correlates with matrix metalloproteinase activity in cartilage explant cultures [J]. Arthritis Rheum,1997,40:164-74.
[44] V Everts, E van der Zee, L Creemers, et al. Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling [J]. Histochem J,1996,28:229-45.
[45] B Dai, Y Cao, J Zhou, et al. Abnormal expression of matrix metalloproteinase-2 and -9 in interspecific pregnancy of rat embryos in mouse recipients [J]. Theriogenology, 2003,60:1279-91.
[46] A Talvensaari-Mattila, P Paakko, T Turpeenniemi-Hujanen. Matrix metalloproteinase-2 (MMP-2) is associated with survival in breast carcinoma [J]. Br J Cancer,2003,89:1270-5.
[47] MS Hibbs, JR Hoidal, AH Kang. Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages [J]. J Clin Invest,1987,80:1644-50.
[48] EH Kerkvliet, AJ Docherty, W Beertsen, et al. Collagen breakdown in soft connective tissue explants is associated with the level of active gelatinase A (MMP-2) but not with collagenase [J]. Matrix Biol,1999,18:373-80.
[49] LB Creemers, IDC Jansen, AJP Docherty, et al. Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue [J]. Matrix Biology,1998,17:35-46.
[50] Q Nguyen, G Murphy, PJ Roughley, et al. Degradation of proteoglycan aggregate by a cartilage metalloproteinase. Evidence for the involvement of stromelysin in the generation of link protein heterogeneity in situ [J]. Biochem J,1989,259:61-7.
[51] K Subramaniam, CM Pech, MC Stacey, et al. Induction of MMP-1, MMP-3 and TIMP-1 in normal dermal fibroblasts by chronic venous leg ulcer wound fluid* [J]. Int Wound J,2008,5:79-86.
[52] K Suzuki, JJ Enghild, T Morodomi, et al. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin) [J]. Biochemistry,1990,29:10261-70.
[53] HB Sun, H Yokota. Reduction of cytokine-induced expression and activity of MMP-1 and MMP-13 by mechanical strain in MH7A rheumatoid synovial cells [J]. Matrix Biol,2002,21:263-70.
[54] P Patwari, J Fay, MN Cook, et al. In vitro models for investigation of the effects of acute mechanical injury on cartilage [J]. Clin Orthop Relat Res,2001:S61-71.
[55] C Yang, M Zeisberg, B Mosterman, et al. Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors [J]. Gastroenterology,2003,124:147-59.
[56] YL He, EJ Macarak, JM Korostoff, et al. Compression and tension: Differential effects on matrix accumulation by periodontal ligament fibroblasts in vitro [J]. Connective Tissue Research,2004,45:28-39.
[57] JM Archambault, MK Elfervig-Wall, M Tsuzaki, et al. Rabbit tendon cells produce MMP-3 in response to fluid flow without significant calcium transients [J]. Journal of Biomechanics,2002,35:303-9.
[58] AH Hsieh, JC Lotz. Prolonged spinal loading induces matrix metalloproteinase-2 activation in intervertebral discs [J]. Spine,2003,28:1781-8.
[59] D Zhou, HS Lee, F Villarreal, et al. Differential MMP-2 activity of ligament cells under mechanical stretch injury: an in vitro study on human ACL and MCL fibroblasts [J]. J Orthop Res,2005,23:949-57.
[60] H Louboutin, R Debarge, J Richou, et al. Osteoarthritis in patients with anterior cruciate ligament rupture: A review of risk factors [J]. Knee,2009,16:239-44.
[61] BE Oiestad, L Engebretsen, K Storheim, et al. Knee Osteoarthritis After Anterior Cruciate Ligament Injury A Systematic Review [J]. Am J Sport Med,2009,37:1434-43.
[62] F Heraud, A Heraud, MF Harmand. Apoptosis in normal and osteoarthritic human articular cartilage [J]. Annals of the Rheumatic Diseases,2000,59:959-65.
[63] T Aigner, A Hemmel, D Neureiter, et al. Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritic human articular knee cartilage - A study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage [J]. Arthritis and Rheumatism,2001,44:1304-12.
[64] GL Semenza, GL Wang. A Nuclear Factor Induced by Hypoxia Via Denovo Protein-Synthesis Binds to the Human Erythropoietin Gene Enhancer at a Site Required for Transcriptional Activation [J]. Molecular and Cellular Biology,1992,12:5447-54.
[65]戴辰程.缺氧诱导因子-1与类风湿关节炎[J].国外医学(免疫学分册),2005:298-302.
[66] NV Iyer, SW Leung, GL Semenza. The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation [J]. Genomics,1998,52:159-65.
[67] GL Semenza. Targeting HIF-1 for cancer therapy [J]. Nat Rev Cancer,2003,3:721-32.
[68] NA Whitlock, N Agarwal, JX Ma, et al. Hsp27 upregulation by HIF-1 signaling offers protection against retinal ischemia in rats [J]. Invest Ophthalmol Vis Sci,2005,46:1092-8.
[69] GL Semenza. HIF-1: mediator of physiological and pathophysiological responses to hypoxia [J]. J Appl Physiol,2000,88:1474-80.
[70] A Weidemann, WM Bernhardt, B Klanke, et al. HIF activation protects from acute kidneyinjury [J]. Journal of the American Society of Nephrology,2008,19:486-94.
[71] RK Bruick, SL McKnight. Transcription - Oxygen sensing gets a second wind [J]. Science,2002,295:807-8.
[72] IR Botusan, VG Sunkari, O Savu, et al. Stabilization of HIF-1 alpha is critical to improve wound healing in diabetic mice [J]. P Natl Acad Sci USA,2008,105:19426-31.
[73] JX Chen, T Zhao, DX Huang. Protective effects of edaravone against cobalt chloride-induced apoptosis in PC12 cells [J]. Neurosci Bull,2009,25:67-74.
[74] GH Altman, HH Lu, RL Horan, et al. Advanced bioreactor with controlled application of multi-dimensional strain for tissue engineering [J]. J Biomech Eng,2002,124:742-9.
[75] J Garvin, J Qi, M Maloney, et al. Novel system for engineering bioartificial tendons and application of mechanical load [J]. Tissue Eng,2003,9:967-79.
[76] G Matziolis, J Tuischer, G Kasper, et al. Simulation of cell differentiation in fracture healing: Mechanically loaded composite scaffolds in a novel bioreactor system [J]. Tissue Engineering,2006,12:201-8.
[77] FG Giancotti. Integrin signaling: specificity and control of cell survival and cell cycle progression [J]. Curr Opin Cell Biol,1997,9:691-700.
[78] KL Sung, DE Whittemore, L Yang, et al. Signal pathways and ligament cell adhesiveness [J]. J Orthop Res,1996,14:729-35.
[79] SP Arnoczky, T Tian, M Lavagnino, et al. Activation of stress-activated protein kinases (SAPK) in tendon cells following cyclic strain: the effects of strain frequency, strain magnitude, and cytosolic calcium [J]. J Orthopaed Res,2002,20:947-52.
[80] SA Park, IA Kim, YJ Lee, et al. Biological responses of ligament fibroblasts and gene expression profiling on micropatterned silicone substrates subjected to mechanical stimuli [J]. J Biosci Bioeng,2006,102:402-12.
[81] J Zeichen, M van Griensven, U Bosch. The proliferative response of isolated human tendon fibroblasts to cyclic biaxial mechanical strain [J]. Am J Sports Med,2000,28:888-92.
[82] G Yang, RC Crawford, JH Wang. Proliferation and collagen production of human patellar tendon fibroblasts in response to cyclic uniaxial stretching in serum-free conditions [J]. J Biomech,2004,37:1543-50.
[83] CH Lee, HJ Shin, IH Cho, et al. Nanofiber alignment and direction of mechanical strain affect the ECM production of human ACL fibroblast [J]. Biomaterials,2005,26:1261-70.
[84] T Toyoda, H Matsumoto, K Fujikawa, et al. Tensile load and the metabolism of anterior cruciate ligament cells [J]. Clin Orthop Relat Res,1998:247-55.
[85] JA Hannafin, SP Arnoczky, A Hoonjan, et al. Effect of stress deprivation and cyclic tensileloading on the material and morphologic properties of canine flexor digitorum profundus tendon: an in vitro study [J]. J Orthop Res,1995,13:907-14.
[86] N Yamamoto, K Ohno, K Hayashi, et al. Effects of stress shielding on the mechanical properties of rabbit patellar tendon [J]. J Biomech Eng,1993,115:23-8.
[87] RC Buck. Reorientation response of cells to repeated stretch and recoil of the substratum [J]. Exp Cell Res,1980,127:470-4.
[88] C Neidlinger-Wilke, E Grood, L Claes, et al. Fibroblast orientation to stretch begins within three hours [J]. J Orthop Res,2002,20:953-6.
[89] C Neidlinger-Wilke, ES Grood, JHC Wang, et al. Cell alignment is induced by cyclic changes in cell length: studies of cells grown in cyclically stretched substrates [J]. J Orthopaed Res,2001,19:286-93.
[90] TW Gilbert, AM Stewart-Akers, J Sydeski, et al. Gene expression by fibroblasts seeded on small intestinal submucosa and subjected to cyclic stretching [J]. Tissue Engineering, 2007,13:1313-23.
[91] JHC Wang, GG Yang, ZZ Li, et al. Fibroblast responses to cyclic mechanical stretching depend on cell orientation to the stretching direction [J]. Journal of Biomechanics, 2004,37:573-6.
[92] JHC Wang, FY Jia, TW Gilbert, et al. Cell orientation determines the alignment of cell-produced collagenous matrix [J]. Journal of Biomechanics,2003,36:97-102.
[93] MS Jones, AJ Banes, ME Wall, et al. Ligament cells stretched on a microgrooved substrate increase intracellular calcium in response to a mechanical stimulus [J]. Mater Res Soc Symp P,2004,1:197-9.
[94] BF Jones, ME Wall, RL Carroll, et al. Ligament cells stretch-adapted on a microgrooved substrate increase intercellular communication in response to a mechanical stimulus [J]. Journal of Biomechanics,2005,38:1653-64.
[95] M Chiquet. Regulation of extracellular matrix gene expression by mechanical stress [J]. Matrix Biology,1999,18:417-26.
[96] AH Hsieh, CMH Tsai, QJ Ma, et al. Time-dependent increases in type-III collagen gene expression in medial collateral ligament fibroblasts under cyclic strains [J]. J Orthopaed Res,2000,18:220-7.
[97] CY Lee, XH Liu, CL Smith, et al. The combined regulation of estrogen and cyclic tension on fibroblast biosynthesis derived from anterior cruciate ligament [J]. Matrix Biology,2004,23:323-9.
[98] T Marui, C Niyibizi, HI Georgescu, et al. Effect of growth factors on matrix synthesis byligament fibroblasts [J]. J Orthopaed Res,1997,15:18-23.
[99] M Skutek, M van Griensven, J Zeichen, et al. Cyclic mechanical stretching modulates secretion pattern of growth factors in human tendon fibroblasts [J]. European Journal of Applied Physiology,2001,86:48-52.
[100] D Amiel, WH Akeson, FL Harwood, et al. Stress Deprivation Effect on Metabolic Turnover of the Medial Collateral Ligament Collagen - a Comparison between 9-Week and 12-Week Immobilization [J]. Clin Orthop Relat R,1983:265-70.
[101] WH Akeson, D Amiel, MF Abel, et al. Effects of Immobilization on Joints [J]. Clin Orthop Relat R,1987:28-37.
[102] D Amiel, SLY Woo, FL Harwood, et al. The Effect of Immobilization on Collagen Turnover in Connective-Tissue - a Biochemical-Biomechanical Correlation [J]. Acta Orthopaedica Scandinavica,1982,53:325-32.
[103] K Hayashi. Biomechanical studies of the remodeling of knee joint tendons and ligaments [J]. Journal of Biomechanics,1996,29:707-16.
[104] K Yasuda, K Hayashi. Changes in biomechanical properties of tendons and ligaments from joint disuse [J]. Osteoarthr Cartilage,1999,7:122-9.
[105] FP Barry. Biology and clinical applications of mesenchymal stem cells [J]. Birth Defects Res C Embryo Today,2003,69:250-6.
[106] U Noth, K Schupp, A Heymer, et al. Anterior cruciate ligament constructs fabricated from human mesenchymal stem cells in a collagen type I hydrogel [J]. Cytotherapy, 2005,7:447-55.
[107] J Chen, RL Horan, D Bramono, et al. Monitoring mesenchymal stromal cell developmental stage to apply on-time mechanical stimulation for ligament tissue engineering [J]. Tissue Eng,2006,12:3085-95.
[108] GH Altman, RL Horan, I Martin, et al. Cell differentiation by mechanical stress [J]. FASEB J,2002,16:270-2.
[109] IC Lee, JH Wang, YT Lee, et al. The differentiation of mesenchymal stem cells by mechanical stress or/and co-culture system [J]. Biochem Bioph Res Co,2007,352:147-52.
[110] N Juncosa-Melvin, JT Shearn, GP Boivin, et al. Effects of mechanical stimulation on the biomechanics and histology of stem cell-collagen sponge constructs for rabbit patellar tendon repair [J]. Tissue Engineering,2006,12:2291-300.
[111] CF Ettlinger, RJ Johnson, JE Shealy. A Method to Help Reduce the Risk of Serious Knee Sprains Incurred in Alpine Skiing [J]. Am J Sport Med,1995,23:531-7.
[112] FR Noyes, PA Mooar, DS Matthews, et al. The Symptomatic Anterior Cruciate-DeficientKnee .1. The Long-Term Functional Disability in Athletically Active Individuals [J]. Journal of Bone and Joint Surgery-American Volume,1983,65:154-62.
[113] FR Noyes, DS Matthews, PA Mooar, et al. The Symptomatic Anterior Cruciate-Deficient Knee .2. The Results of Rehabilitation, Activity Modification, and Counseling on Functional Disability [J]. Journal of Bone and Joint Surgery-American Volume,1983,65:163-74.
[114] DA Bettinger, JV Pellicane, WC Tarry, et al. The Role of Inflammatory Cytokines in Wound-Healing - Accelerated Healing in Endotoxin-Resistant Mice [J]. Journal of Trauma-Injury Infection and Critical Care,1994,36:810-3.
[115] CA Dinarello. The Interleukin-1 Family - 10 Years of Discovery [J]. Faseb Journal,1994,8:1314-25.
[116] DP Mooney, M Oreilly, RL Gamelli. Tumor Necrosis Factor and Wound-Healing [J]. Annals of Surgery,1990,211:124-9.
[117] NG Frangogiannis, CW Smith, ML Entman. The inflammatory response in myocardial infarction [J]. Cardiovascular Research,2002,53:31-47.
[118] FC Iwuagwu, DA McGrouther. Early cellular response in tendon injury: The effect of loading [J]. Plastic and Reconstructive Surgery,1998,102:2064-71.
[119] D Marsolais, CH Cote, J Frenette. Neutrophils and macrophages accumulate sequentially following Achilles tendon injury [J]. J Orthop Res,2001,19:1203-9.
[120] RB Mateo, JS Reichner, JE Albina. Interleukin-6 activity in wounds [J]. Am J Physiol,1994,266:R1840-4.
[121] RM Gallucci, PP Simeonova, JM Matheson, et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice [J]. FASEB J,2000,14:2525-31.
[122] RG Holzheimer, W Steinmetz. Local and systemic concentrations of pro- and anti-inflammatory cytokines in human wounds [J]. Eur J Med Res,2000,5:347-55.
[123] MS Agren. Gelatinase activity during wound healing [J]. Br J Dermatol,1994,131:634-40.
[124] H Nagase, R Visse, G Murphy. Structure and function of matrix metalloproteinases and TIMPs [J]. Cardiovasc Res,2006,69:562-73.
[125] R Visse, H Nagase. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry [J]. Circ Res,2003,92:827-39.
[126] MJ Foos, JR Hickox, PG Mansour, et al. Expression of matrix metalloprotease and tissue inhibitor of metalloprotease genes in human anterior cruciate ligament [J]. J Orthop Res,2001,19:642-9.
[127] AB Wysocki, L Staianocoico, F Grinnell. Wound Fluid from Chronic Leg Ulcers Contains Elevated Levels of Metalloproteinases Mmp-2 and Mmp-9 [J]. Journal of InvestigativeDermatology,1993,101:64-8.
[128] E Louis, KA Remer, MG Doherr, et al. Nitric oxide and metalloproteinases in canine articular ligaments: a comparison between the cranial cruciate, the medial genual collateral and the femoral head ligament [J]. Vet J,2006,172:466-72.
[129] P Muir, PA Manley, Z Hao. Collagen fragmentation in ruptured canine cranial cruciate ligament explants [J]. Vet J,2006,172:121-8.
[130] MPH Le Graverand, J Eggerer, P Sciore, et al. Matrix metalloproteinase-13 expression in rabbit knee joint connective tissues: influence of maturation and response to injury [J]. Matrix Biology,2000,19:431-41.
[131] GS Firestein. Evolving concepts of rheumatoid arthritis [J]. Nature,2003,423:356-61.
[132] T Pap, WH van der Laan, KR Aupperle, et al. Modulation of fibroblast-mediated cartilage degradation by articular chondrocytes in rheumatoid arthritis [J]. Arthritis Rheum,2000,43:2531-6.
[133] F De Benedetti, P Pignatti, V Gerloni, et al. Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis [J]. J Rheumatol,1997,24:1403-9.
[134] JHW Distler, A Jungel, LC Huber, et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles [J]. P Natl Acad Sci USA,2005,102:2892-7.
[135] TN Trumble, GW Trotter, JR Oxford, et al. Synovial fluid gelatinase concentrations and matrix metalloproteinase and cytokine expression in naturally occurring joint disease in horses [J]. Am J Vet Res,2001,62:1467-77.
[136] EJ Barone, DR Yager, AL Pozez, et al. Interleukin-1alpha and collagenase activity are elevated in chronic wounds [J]. Plast Reconstr Surg,1998,102:1023-7; discussion 8-9.
[137] F Quatra, MR Colonna, A Catalano. The role of interleukin-1alpha and collagenase in chronic wounds [J]. Plast Reconstr Surg,1999,104:1205-6.
[138] TS Momberger, JR Levick, RM Mason. Hyaluronan secretion by synoviocytes is mechanosensitive [J]. Matrix Biology,2005,24:510-9.
[139] Z Tang, L Yang, R Xue, et al. Differential expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in anterior cruciate ligament and medial collateral ligament fibroblasts after a mechanical injury: involvement of the p65 subunit of NF-kappaB [J]. Wound Repair Regen,2009,17:709-16.
[140] AA Lee, T Delhaas, LK Waldman, et al. An equibiaxial strain system for cultured cells [J]. Am J Physiol,1996,271:C1400-8.
[141] AA Lee, T Delhaas, AD McCulloch, et al. Differential responses of adult cardiac fibroblaststo in vitro biaxial strain patterns [J]. J Mol Cell Cardiol,1999,31:1833-43.
[142] J Zhang, L Yang, Z Tang, et al. Expression of MMPs and TIMPs Family in Human ACL and MCL Fibroblasts [J]. Connective Tissue Research,2009,50:7-13.
[143] M Tsuzaki, G Guyton, W Garrett, et al. IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells [J]. J Orthop Res,2003,21:256-64.
[144] W Petersen, B Tillmann. Structure and vascularization of the cruciate ligaments of the human knee joint [J]. Anat Embryol (Berl),1999,200:325-34.
[145] TD Warner, JA Mitchell. HIF, stretching to get control of VEGF [J]. Clin Sci (Lond),2003,105:393-4.
[146] KH Hong, SA Yoo, SS Kang, et al. Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts [J]. Clin Exp Immunol,2006,146:362-70.
[147] W Petersen, D Varoga, T Zantop, et al. Cyclic strain influences the expression of the vascular endothelial growth factor (VEGF) and the hypoxia inducible factor 1 alpha (HIF-1 alpha) in tendon fibroblasts [J]. J Orthopaed Res,2004,22:847-53.
[148] AA Tandara, TA Mustoe. Oxygen in wound healing--more than a nutrient [J]. World J Surg,2004,28:294-300.
[149] H Kofoed. Synovitis causes hypoxia and acidity in synovial fluid and subchondral bone [J]. Injury,1986,17:391-4.
[150] HS Cha, KS Ahn, CH Jeon, et al. Influence of hypoxia on the expression of matrix metalloproteinase-1, -3 and tissue inhibitor of metalloproteinase-1 in rheumatoid synovial fibroblasts [J]. Clin Exp Rheumatol,2003,21:593-8.
[151] EA Ayello, JE Cuddigan. Conquer chronic wounds with wound bed preparation [J]. Nurse Pract,2004,29:8-25; quiz 6-7.
[152] GM Gordillo, CK Sen. Revisiting the essential role of oxygen in wound healing [J]. American Journal of Surgery,2003,186:259-63.
[153] Z Wood. Hyperbaric oxygen in the management of chronic wounds [J]. Br J Nurs,2002,11:S16, S8-9, S22-4.
[154] JA Thackham, DLS McElwain, RJ Long. The use of hyperbaric oxygen therapy to treat chronic wounds: A review [J]. Wound Repair and Regeneration,2008,16:321-30.
[155] TD Ardyanto, M Osaki, N Tokuyasu, et al. CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway [J]. Int J Oncol,2006,29:549-55.
[156] F Heraud, A Heraud, MF Harmand. Apoptosis in normal and osteoarthritic human articular cartilage [J]. Ann Rheum Dis,2000,59:959-65.
[157] T Aigner, M Hemmel, D Neureiter, et al. Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage [J]. Arthritis Rheum,2001,44:1304-12.
[158]韩建群,余明华,戴旻, et al.氯化钴化学模拟低氧对肿瘤细胞增殖及凋亡的影响[J].基础医学与临床,2008:867-72.
[159] D Amiel, E Billings, Jr., FL Harwood. Collagenase activity in anterior cruciate ligament: protective role of the synovial sheath [J]. J Appl Physiol,1990,69:902-6.
[160] EC Finger, AJ Giaccia. Hypoxia, inflammation, and the tumor microenvironment in metastatic disease [J]. Cancer Metastasis Rev,2010,29:285-93.
[161] S Kondo, S Kubota, T Shimo, et al. Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases [J]. Carcinogenesis,2002,23:769-76.
[162] RF Diegelmann, MC Evans. Wound healing: An overview of acute, fibrotic and delayed healing [J]. Frontiers in Bioscience,2004,9:283-9.
[163] AB Wysocki, AO Kusakabe, S Chang, et al. Temporal expression of matrix metalloproteinase-9 and urokinase plasminogen activator in human chronic wound fluids. [J]. Molecular Biology of the Cell,1998,9:420a-a.
[164] AB Wysocki, AO Kusakabe, S Chang, et al. Temporal expression of urokinase plasminogen activator, plasminogen activator inhibitor and gelatinase-B in chronic wound fluid switches from a chronic to acute wound profile with progression to healing [J]. Wound Repair and Regeneration,1999,7:154-65.
[165] J Westermarck, VM Kahari. Regulation of matrix metalloproteinase expression in turner invasion [J]. Faseb Journal,1999,13:781-92.
[166] H Nagase, JF Woessner, Jr. Matrix metalloproteinases [J]. J Biol Chem,1999,274:21491-4.
[167] M Karin, Z Liu, E Zandi. AP-1 function and regulation [J]. Curr Opin Cell Biol,1997,9:240-6.
[168] X Wang, T Mori, JC Jung, et al. Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase [J]. J Neurotrauma,2002,19:615-25.
[169] JHC Wang, BP Thampatty, JS Lin, et al. Mechanoregulation of gene expression in fibroblasts [J]. Gene,2007,391:1-15.
[170] Z Han, DL Boyle, AM Manning, et al. AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen-induced arthritis [J]. Autoimmunity,1998,28:197-208.
[171] X Dolcet, D Llobet, J Pallares, et al. NF-kB in development and progression of human cancer [J]. Virchows Archiv,2005,446:475-82.
[172] HK Eltzschig, P Carmeliet. Mechanisms of Disease: Hypoxia and Inflammation. [J]. New Engl J Med,2011,364:656-65.
[173] HK Eltzschig. Targeting Hypoxia-induced Inflammation [J]. Anesthesiology, 2011, 114:239-42.
[174] P Wang, X You, Y Yan, et al. Cyclic mechanical stretch downregulates IL-1 beta-induced COX-2 expression and PGE(2) production in rheumatoid arthritis fibroblast-like synoviocytes [J]. Connective Tissue Research,2011,52:190-7.
[175] JH Wang, BP Thampatty, JS Lin, et al. Mechanoregulation of gene expression in fibroblasts [J]. Gene,2007,391:1-15.
[176] Y Wang, Z Tang, R Xue, et al. TGF-beta1 promoted MMP-2 mediated wound healing of anterior cruciate ligament fibroblasts through NF-kappaB [J]. Connect Tissue Res,2011,52:218-25.
[177] F Mannello. Serum or plasma samples? The "Cinderella" role of blood collection procedures: preanalytical methodological issues influence the release and activity of circulating matrix metalloproteinases and their tissue inhibitors, hampering diagnostic trueness and leading to misinterpretation [J]. Arterioscler Thromb Vasc Biol,2008,28:611-4.