Document Detail

Action mechanisms of du-huo-ji-sheng-tang on cartilage degradation in a rabbit model of osteoarthritis.
Jump to Full Text
MedLine Citation:
PMID:  21792361     Owner:  NLM     Status:  In-Data-Review    
Du-Huo-Ji-Sheng-Tang (DHJST) is a traditional Chinese herbal medicine used to treat osteoarthritis. In the present study, the therapeutic effect of DHJST on cartilage degradation in a rabbit model of osteoarthritis was investigated. In the knee joints of rabbits, anterior cruciate ligament transection (ACLT) was performed to induce experimental osteoarthritis. At the end of the sixth week, 30 rabbits with ACLT were divided into six groups, control group, DHJST group and Osaminethacine (OSA) group, which were followed for another 4 weeks. The other three groups of rabbits with ACLT were untreated with DHJST or OSA, which were sacrificed after 6 weeks, and served as 6-week time point controls. Results indicated that at the end of the sixth week after surgery, there was a significantly histological degeneration in the control group compared with the normal group. In the control group, the mean score for histological degeneration were further increases at 10th week, and there was a significantly lower mean score for histological degeneration in the DHJST group compared with the control group. To research the potential mechanism, the expression level of VEGF and HIF-1α were detected. The expression of VEGF mRNA and HIF-1α mRNA are low in normal group, while the activities increase gradually in the control group. However, compared to that of the same time point model group, activity of VEGF and HIF-1α decreased significantly in DHJST group. In conclusion, DHJST exerts significant therapeutic effect on osteoarthritis rabbits, and mechanisms are associated with inhibition of VEGF and HIF-1α expression.
Chao-Wei Chen; Jian Sun; Yu-Mei Li; Pi-An Shen; Yong-Qiang Chen
Publication Detail:
Type:  Journal Article     Date:  2011-03-20
Journal Detail:
Title:  Evidence-based complementary and alternative medicine : eCAM     Volume:  2011     ISSN:  1741-4288     ISO Abbreviation:  Evid Based Complement Alternat Med     Publication Date:  2011  
Date Detail:
Created Date:  2011-07-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101215021     Medline TA:  Evid Based Complement Alternat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  571479     Citation Subset:  -    
Department of Orthopaedics and Traumatology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai 200071, China.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Evid Based Complement Alternat Med
Journal ID (publisher-id): ECAM
ISSN: 1741-427X
ISSN: 1741-4288
Publisher: Hindawi Publishing Corporation
Article Information
Download PDF
Copyright © 2011 Chao-Wei Chen et al.
Received Day: 26 Month: 4 Year: 2009
Accepted Day: 29 Month: 12 Year: 2009
Print publication date: Year: 2011
Electronic publication date: Day: 20 Month: 3 Year: 2011
pmc-release publication date: Day: 20 Month: 3 Year: 2011
Volume: 2011E-location ID: 571479
ID: 3136681
PubMed Id: 21792361
DOI: 10.1093/ecam/neq002

Action Mechanisms of Du-Huo-Ji-Sheng-Tang on Cartilage Degradation in a Rabbit Model of Osteoarthritis
Chao-Wei ChenI1
Jian SunI1
Yu-Mei LiI1
Pi-An ShenI1
Yong-Qiang ChenI1*
Department of Orthopaedics and Traumatology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai 200071, China
Correspondence: *Yong-Qiang Chen:

1. Introduction

Osteoarthritis (OA) is a progressive and debilitating disease that may take years to clinically manifest in affected individuals. Cartilage aging and chondrocyte senescence play an important role in the pathogenesis and development of OA. During the development of OA, there is often a focal increase in cell death. Lots of reports revealed that chondrocyte senescence contributes to the risk of cartilage degeneration by decreasing the ability of chondrocytes to maintain and repair the articular cartilage tissue [1, 2]. Since it is theorized that each chondrocyte is responsible for the maintenance of the extracellular matrix surrounding it, and that matrix molecules produced in one region of the tissue have a very limited ability to traverse the tissue, the focal loss of viable cells could be partially responsible for the tissues inability to repair minor damage [3].

Currently, there is not a cure for OA, and available treatments only slow the progression of disease [46]. For the last 20 years, Traditional Chinese Medicine (TCM) has seen significant advancement against OA, such as in improving patients' clinical findings, inhibiting inflammatory reaction and cartilage degeneration [7, 8]. In vivo and in vitro study also showed that Chinese herbs formula is of multiple comprehensive actions against OA [912]. Du-Huo-Ji-Sheng-Tang, which is composed of Radix Angelicae Pubescentis, Herba Taxilli, Herba Taxilli, Radix Acanthopanacis Bidentatae, Herba Asari, Radix Gentianae Macrophyllae, Cortex Cinnamomi and Poria, has been widely used for treating OA. It can improve clinical symptoms, knee function and quality of life for patients [13]. Based on our knowledge about OA pathogenesis in TCM, we investigated the effect of DHJST on preventing cartilage degeneration of OA in rabbits and observed its mechanisms.

2. Methods
2.1. Materials

The Dead End colorimetric apoptosis detection system (TUNEL assay) was obtained from Nanjing Jiancheng Biotech Company (China). Trizol total RNA extraction kit, DNA molecular marker, SYBR Premix EX TaqTM and Perfect Real Time kit were purchased from the Invitrogen Co. (USA). Herbs in DJST (composed of Radix Angelicae Pubescentis, Herba Taxilli, Herba Taxilli, Radix Acanthopanacis Bidentatae, Herba Asari, Radix Gentianae Macrophyllae, Cortex Cinnamomi and Poria, provided by Shanghai Huayu Chinese Herbs Co. Ltd., China) were accredited by a pharmacognosist according to standard protocols, prepared by Shanghai Municipal Hospital of Traditional Chinese Medicine, the components were mixed in order with the ratio of 2 : 1 : 1 : 1 : 0.2 : 1 : 0.3 : 1 (dry weight), The drugs were extracted with standard methods according to Chinese Pharmacopoeia (China Pharmacopoeia and Committee, 2000). These crude drugs were soaked in distilled water and boiled for 30 min twice, and the drug solution was filtered through a mesh, then the filtrate was concentrated to 4 g mL−1 by a vacuum pump and then stored at –20°C until use. Osaminethacine (OSA), each tablet contains 25 mg indomethacin and 75 mg aminoglucose (supplied by Hebei Jizhong Pharmaceutical Co. Ltd., China), was used as positive control medicine.

2.2. Rabbits and Tissue Preparation

Forty-eight-month-old New Zealand white rabbits were supplied by the Experimental Animal Centre to Chinese Academy of Science. Thirty rabbits underwent unilateral anterior cruciate ligament transection (ACLT) under general anesthesia. The normal rabbits did not undergo a procedure.

At the end of the sixth week, the 30 rabbits with ACLT were divided into six groups, control group, DHJST group and OSA group, which were followed for another 4 weeks. The other three groups of rabbits with ACLT were untreated with DHJST or OSA, which were sacrificed after 6 weeks, and served as 6-week time point controls. The decoctions were orally administrated at dosage 0.923 g (kg−1·d−1) for 4 weeks, rabbits in the OSA group were administered OSA 0.09 g (kg−1·d−1) for a period of 4 weeks, model control group and normal group were orally administrated with same volume of physiological saline.

Rabbits were sacrificed for sampling. The protocol received approval of the committee for Animal Experiments of the University Medical Centre, Shanghai, China. Rabbit tibiae was removed and tibia articular cartilage was immediately stored at –80°C. The tibiae were carefully dissected and cleared from adjacent muscle and immediately fixed in 10% formalin for 24 hours. Tibiae were subsequently decalcified for 4 weeks in 100 g/L ethylenediamine tetraacetic acid, washed in PBS, dehydrated through a series of ethanol and embedded in paraffin in a standardized way to ensure proper orientation. Paraffin tissue sections (7 μm) were cut in a standardized way. Sections were deparaffinized for histochemical analyses.

2.3. Histological Assessment of Cartilage

Histological assessment was performed on the femorotibial joints of rabbits in the DHJST group, OSA group and control groups. The sections were stained with Safranin O-fast green. These histological sections from each site were evaluated using a modified Mankin grading system [14] (Table 1) by two independent, board-certified veterinary pathologists.

2.4. TUNEL Assay

H2O2-induced apoptosis was detected by performing the terminal deoxynucleotidedyl transferase-mediated dUTP nick end-labeling (TUNEL) assay using an Apo-DirectTM Kit (CalBiochem, San Diego, CA). TUNEL was performed according to the manufacturer's instructions. Briefly, after pretreatments and exposure to H2O2, cells were harvested, washed, fixed, permeabilized and labeled for DNA strand breaks, then analyzed on a Coulter Epics Elite flow cytometer (Beckman-Coulter, Miami, USA). All assays were carried out in triplicate.

2.5. Fluorescent Quantitative PCR

Total RNA was extracted from 50 mg of cartilage in tibiae articular using Trizol reagent. Synthesis of cDNA was performed using 4 μg of total RNA per sample with random primers and reagents contained in the Revert Aid First Strand cDNA synthesis kit. Two micro liters (2 μL) of each sample was used for real-time PCR in a Rotor-Gene 2000 system (Australia). Relative quantitation was calculated using delta cycle threshold (CT) relative quantitation. The threshold cycle (CT) for the endogenous control CAPDH mRNA and the target signals were determined, and the relative RNA quantification was calculated using comparative 2−ΔΔCt method [15] where ΔΔCt = (CT,Target  − CT,GAPDH )responder − (CT,Target  − CT,GAPDH )not-responder

  •   Sequences of primers used for vascular endothelial growth factor (VEGF) are: 5′-TGCCCACCGAGGAGTTCA-3(forward) and 5′-GGCCCTGGTGAGGTTTGAT-3(reverse) (product length: 75 bp).
  •   Sequences of primers used for hypoxia-inducible factor-1α (HIF-1α) are: 5′-CAGTGCAAAAGACAGGTGGAAG-3(forward) and 5′-CCCTGTATGGTGGTGATGTTGT-3(reverse) (product length: 107 bp).
  •   Sequences of primers used for GAPDH are: 5′-CCGAGGGCCCACTAAAGG-3(forward) and 5′-GCTGTTGAAGTCACAGGAGACAA-3(reverse) (product length: 88 bp).

2.6. Statistical Analysis

All results were expressed as mean and standard deviation (SD). Measurement data were analyzed using a one-way analysis of variances (ANOVA, SPSS 11.0). Rank data were analyzed with ridit. The result of P < .05 was considered to be statistically significant.

3. Results
3.1. ACLT-Induced Histological Degeneration in Rabbits Were Reduced by DHJST

Representative histological sections are shown in Figure 1. At the end of 10th week, we observed a normal integrity of the articular surface in normal group (Figure 1(a)). In control group, with increased degeneration, there was a loss of Safranin O-fast green staining accompanying cleft formation that extended into the middle and deep zones (Figure 1(b)), and in DHJST group, there was lost with early mild fibrillation, and a loss of Safranin O-fast green staining was observed along with chondrocyte clustering (Figure 1(c)). OSA group, with loss of Safranin O-fast green staining these changes were similar to DHJST group (Figure 1(d)). At the end of the sixth week after surgery, there was a significantly histological differences in the control group compared with the normal group (P < .01). In the control group, the mean score for Safranin O-fast green staining were further increases at 10th week in comparison with that of at the 6th week (P < .01) (Figure 2(a)). At 10th weekend, there were significant differences in Mankin score between control group and DHJST group, there was a significantly lower mean score for Safranin O-fast green staining in the DHJST group compared with the control group (P < .01) (Figure 2(b)), and no statistically significant differences in the Mankin score between DHJST group and OSA group (P >.05).

3.2. DHJST Inhibited Cartilage Cells Apoptosis

At the end of the sixth week after surgery, the index of apoptosis cell in the control group compared with that in the normal group were significantly differences (P < .01). In the control group, the index of apoptosis cell was still greatly increased (from mean ± SD 0.35 ± 0.13 at the sixth week to 0.62 ± 0.10 at the 10th week; P < .01) (Figure 2(c)). At the end of 10th week, compared with DHJST group, the index of apoptosis cell increases remarkably in the control group (P < .01) (Figure 2(d)). There were no significant differences in apoptosis cell index between OSA group and DHJST group (P >.05).

3.3. Inhibition of VEGF and HIF-1α Expression in Cartilage Cells Are Associated with DHJST Exerts Therapeutic Effect

Fluorescent quantitative PCR indicated that the expression of VEGF mRNA and HIF-1α mRNA are low in normal group; while the activities increase gradually and significantly in the control group in comparison with that of normal group (P < .01); In control group, HIF-1α in articular chondrocytes begins to increase at the sixth week after surgery, further increases at 10th week in comparison with that of at the sixth week (mean ± SD 94.21 ± 20.12 at the sixth week, and 160.35 ± 72.27 at the 10th week; P < .05) (Table 2). At 10th weekend, The expression of VEGF mRNA and HIF-1α mRNA in DHJST group was significantly decreased as compared with that in control group after administration (P < .01). Although the VEGF mRNA and HIF-1α mRNA level in OSA group tended to be reduced by 4 weeks of OSA treatment as compared with that in control group, there was no significant difference (Table 3).

4. Discussion

The ACLT model is one of the most widely used experimental models of OA. Rabbit ACLT is increasingly being used in OA studies [16] because disease onset is rapid. The use of experimental ACLT models is of particular clinical relevance, since rupture of the ACL occurs in humans and also leads to the development of OA. Study indicates that large amount of chondrocytes apoptosis exists during progressive stage of OA in rabbits induced by surgery. Chondrocyte apoptosis is one of the characteristic changes of OA cartilage. Pathological apoptosis under the condition of harmful stimulation could result in the release of chemotaxis or inflammatory factors, which in turn aggravates cartilage injury and activates pain [17]. Therefore, chondrocyte apoptosis inhibiting might be an important strategy against degenerative changes in rabbits knee joints. Chondrocytes apoptosis index in DHJST group significantly decreases in comparison with that of in the model group, suggesting that inhibition of chondrocyte apoptosis might be one of the important mechanisms of DHJST against degenerative changes.

Previous studies have shown the hypoxic nature of the articular chondrocytes' microenvironment. Interestingly, osteoarthritic joints displayed further decreased oxygen levels, role of hypoxia during the pathogenesis of OA [18]. A recent study described that in articular chondrocytes catabolic and hypoxic stress are strong inducers of the transcription factor HIF-1, which is the principal regulator of cellular adaptation to low oxygen levels. HIF-1 is of pivotal importance for survival and growth arrest of chondrocytes during cartilage development as well as energy generation and matrix synthesis of chondrocytes in healthy as well as osteoarthritic cartilage. In osteoarthritic cartilage, the protein levels of HIF-1 are significantly increased and its activity correlates to the severity of degenerative cartilage changes [1924]. The present work documents the importance of the transcription factor HIF-1α for maintaining the integrity of hypoxic articular cartilage. The surplus levels of HIF-1α coincided with increased apoptosis of articular chondrocytes and led to degenerative changes in rabbits knee joints. After administration of DHJST, HIF-1α expression decreases, in comparison with that of model group. The results show that action of DHJST on regulating function of chondrocytes, might through inhibiting activity of HIF-1α.

It is interesting that the different of the expression of VEGF and HIF-1α between DHJST group and OSA group is significant after administration. Several studies have demonstrated that certain nonsteroidal anti-inflammatory drugs, such as indomethacin, cause anti-inflammatory effects independent of HIF-1α activity, because indomethacin failed to inhibit phosphatidylinositol 3-kinase or extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, as well as Erk activity [25]. In contrast, indomethacin is able to activate peroxisome proliferator-activated receptor-γ, which is not sensitive to sodium salicylate or aspirin. Inhibition of phosphatidylinositol 3-kinase or Erk pathway is related to inhibition of HIF-1α and angiogenic factors [26].

Hypoxia and various growth factors/cytokines enhance VEGF expression [2730]. VEGF is not only one of the most important angiogenesis factors, but is involved also in inflammatory processes in OA and contribute to symptoms such as pain and swelling by targeting the synovial membranes [3134], chronic inflammatory responses are often associated with the production of angiogenic factors that induce vascular proliferation, and in rheumatoid arthritis VEGF is highly expressed in synovial cells [3540]. Since mechanical overload is one of the causative factors for OA, we studied its effect on VEGF expression on rabbit's cartilage that the expression of VEGF decreases after administration of DHJST, the result indicates that DHJST can protect the articular cartilage through suppressing the VEGF expression in chondrocytes (Figure 3).

5. Conclusions

Up to now, the bioactive ingredients in DHJST is unknown, but our study indicates that DHJST exerts significant therapeutic effect on OA in rabbits, through mechanisms of inhibiting chondrocytes apoptosis, and regulating the expression of VEGF, HIF-1α in chondrocytes. This provides scientific evidence for clinic to apply DHJST in treating OA.


The Natural Science Foundation of Shanghai (grant number: 08JC1418800).

1. Johnson EO,Charchandi A,Babis GC,Soucacos PN. Apoptosis in osteoarthritis: morphology, mechanisms, and potential means for therapeutic interventionJournal of surgical orthopaedic advancesYear: 200817314715218851798
2. Bos SD,Slagboom PE,Meulenbelt I. New insights int osteoarthritis: early developmental features of an ageing-related diseaseCurrent Opinion in RheumatologyYear: 200820555355918698177
3. Sandell LJ,Aigner T. Articular cartilage and changes in arthritis an introduction: cell biology of osteoarthritisArthritis ResearchYear: 20013210711311178118
4. Ahmed S,Anuntiyo J,Malemud CJ,Haqqi TM. Biological basis for the use of botanicals in osteoarthritis and rheumatoid arthritis: a reviewEvidence-Based Complementary and Alternative MedicineYear: 20052330130816136208
5. Edmonds S. Therapeutic targets for osteoarthritisMaturitasYear: 200963319119419423245
6. Altman RD,Barkin RL. Topical therapy for osteoarthritis: clinical and pharmacologic perspectivesPostgraduate MedicineYear: 2009121213914719332972
7. Parkman CA. Alternative therapies for osteoarthritisCase ManagerYear: 2001123343611351231
8. Teekachunhatean S,Kunanusorn P,Rojanasthien N,et al. Chinese herbal recipe versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial [ISRCTN70292892]BMC Complementary and Alternative MedicineYear: 20044, article 19
9. Frondoza CG,Sohrabi A,Polotsky A,Phan PV,Hungerford DS,Lindmark L. An in vitro screening assay for inhibitors of proinflammatory mediators in herbal extracts using human synoviocyte culturesIn Vitro Cellular and Developmental Biology—AnimalYear: 2004403-49510115311968
10. Setty AR,Sigal LH. Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effectsSeminars in Arthritis and RheumatismYear: 200534677378415942912
11. Chun S-C,Jee SY,Lee SG,Park SJ,Lee JR,Kim SC. Anti-inflammatory activity of the methanol extract of Moutan Cortex in LPS-activated Raw264.7 cellsEvidence-Based Complementary and Alternative MedicineYear: 20074332733317965763
12. Wu M,Gu Z. Screening of bioactive compounds from Moutan Cortex and their anti-inflammatory activities in rat synoviocytesEvidence-Based Complementary and Alternative MedicineYear: 200961576318955220
13. Lai JN,Chen H-J,Chen C-C,Lin J-H,Hwang J-S,Wang J-D. Duhuo Jisheng Tang for treating osteoarthritis of the knee: a prospective clinical observationChinese MedicineYear: 20072, article 4
14. van der Sluijs JA,Geesink RGT,van der Linden AJ,Bulstra SK,Kuyer R,Drukker J. The reliability of the Mankin score for osteoarthritisJournal of Orthopaedic ResearchYear: 199210158611727936
15. Livak KJ,Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT methodMethodsYear: 200125440240811846609
16. Sonoda M,Harwood FL,Amiel ME,Moriya H,Amiel D. The effects of hyaluronan on the meniscus in the anterior cruciate ligament-deficient kneeJournal of Orthopaedic ScienceYear: 20005215716410982650
17. Takahashi K,Hashimoto S,Kubo T,Hirasawa Y,Lotz M,Amiel D. Effect of hyaluronan on chondrocyte apoptosis and nitric oxide production in experimentally induced osteoarthritisJournal of RheumatologyYear: 20002771713172010914857
18. Pfander D,Gelse K. Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environmentsCurrent Opinion in RheumatologyYear: 200719545746217762611
19. Wiesener MS,Maxwell PH. HIF and oxygen sensing; as important to life as the air we breathe?Annals of MedicineYear: 200335318319012822740
20. Adesida AB,Grady LM,Khan WS,Millward-Sadler SJ,Salter DM,Hardingham TE. Human meniscus cells express hypoxia inducible factor-1α and increased SOX9 in response to low oxygen tension in cell aggregate cultureArthritis Research and TherapyYear: 200794, article R69
21. Semenza GL. Hif-1 and human disease: one highly involved factorGenes and DevelopmentYear: 200014161983199110950862
22. Giatromanolaki A,Sivridis E,Maltezos E,et al. Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritisArthritis Research &amp; TherapyYear: 200354R19320112823854
23. Brucker PU,Izzo NJ,Chu CR. Tonic activation of hypoxia-inducible factor 1α in avascular articular cartilage and implications for metabolic homeostasisArthritis and RheumatismYear: 200552103181319116200622
24. Grimmer C,Balbus N,Lang U,et al. Regulation of type II collagen synthesis during osteoarthritis by prolyl-4-hydroxylases: possible influence of low oxygen levelsAmerican Journal of PathologyYear: 2006169249150216877351
25. Tsutsumi R,Ito H,Hiramitsu T,et al. Celecoxib inhibits production of MMP and NO via down-regulation of NF-κB and JNK in a PGE2 independent manner in human articular chondrocytesRheumatology InternationalYear: 200828872773618080123
26. Won J-H,Im H-T,Kim Y-H,et al. Anti-inflammatory effect of buddlejasaponin IV through the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via the NF-κB inactivationBritish Journal of PharmacologyYear: 2006148221622516520738
27. Pufe T,Lemke A,Kurz B,et al. Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factorAmerican Journal of PathologyYear: 2004164118519214695332
28. Walsh DA. Pathophysiological mechanisms of angiogenesisAdvances in Clinical ChemistryYear: 20074418722117682343
29. Walsh DA,Bonnet CS,Turner EL,Wilson D,Situ M,McWilliams DF. Angiogenesis in the synovium and at the osteochondral junction in osteoarthritisOsteoarthritis and CartilageYear: 200715774375117376709
30. Walsh DA. Angiogenesis and arthritisRheumatologyYear: 199938210311210342621
31. Maes C,Stockmans I,Moermans K,et al. Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survivalJournal of Clinical InvestigationYear: 2004113218819914722611
32. Smith JO,Oreffo ROC,Clarke NMP,Roach HI. Changes in the antiangiogenic properties of articular cartilage in osteoarthritisJournal of Orthopaedic ScienceYear: 20038684985714648276
33. Ruegg C,Mariotti A. Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesisCellular and Molecular Life SciencesYear: 20036061135115712861381
34. Taoufik E,Petit E,Divoux D,et al. TNF receptor I sensitizes neurons to erythropoietin-and VEGF-mediated neuroprotection after ischemic and excitotoxic injuryProceedings of the National Academy of Sciences of the United States of AmericaYear: 2008105166185619018413601
35. Pfander D,Swoboda B,Cramer T. The role of HIF-1α in maintaining cartilage homeostasis and during the pathogenesis of osteoarthritisArthritis Research and TherapyYear: 200681, article 104
36. Park CC,Morel JCM,Amin MA,Connors MA,Harlow LA,Koch AE. Evidence of IL-18 as a novel angiogenic mediatorJournal of ImmunologyYear: 2001167316441653
37. Hashimoto A,Tarner IH,Bohle RM,et al. Analysis of vascular gene expression in arthritic synovium by laser-mediated microdissectionArthritis and RheumatismYear: 20075641094110517393418
38. Bonnet CS,Walsh DA. Osteoarthritis, angiogenesis and inflammationRheumatologyYear: 200544171615292527
39. Murata M,Yudoh K,Nakamura H,et al. Distinct signaling pathways are involved in Hypoxia- and IL-1-induced VEGF expression in human articular chondrocytesJournal of Orthopaedic ResearchYear: 20062471544155416732616
40. Mapp PI,Avery PS,McWilliams DF,et al. Angiogenesis in two animal models of osteoarthritisOsteoarthritis and CartilageYear: 2008161616917659886

Article Categories:
  • Original Article

Previous Document:  The roles of buyang huanwu decoction in anti-inflammation, antioxidation and regulation of lipid met...
Next Document:  Quercetin and cancer chemoprevention.