Qiming Fan

Renji Hospital, Shanghai, Shanghai Shi, China

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Publications (15)77.03 Total impact

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    ABSTRACT: Osteoporosis is one of the most prevalent skeletal system diseases; yet, its pathophysiological mechanisms remain elusive. Adipocytes accumulate remarkably in the bone marrow of osteoporotic patients. The potential processes and molecular mechanisms underlying adipogenesis in osteoporotic BMSCs have attracted significant attention as adipocytes and osteoblasts share common precursor cells. Some environmental factors influence bone mass through epigenetic mechanisms; however, the role of epigenetic modifications in osteoporosis is just beginning to be investigated, and there is still little data regarding their involvement. In the current study, we investigated how epigenetic modifications, including DNA methylation and histone modifications, lead to adipogenesis in the bone marrow during osteoporosis. A glucocorticoid-induced osteoporosis (GIO) mouse model was established, and BMSCs were isolated from the bone marrow. Compared with normal BMSCs, osteoporotic BMSCs had significantly increased adipogenesis potential and decreased osteogenesis potential. In osteoporotic BMSCs, PPARγ2 regulatory region DNA hypo-methylation, histone 3 and 4 hyper-acetylation and H3K9 hypo-di-methylation were observed. These epigenetic modifications were involved not only in PPARγ2 expression but also in osteoporotic BMSC adipogenic differentiation potential. We also found that Wnt/β-catenin signal played an important role in the establishment and maintenance of epigenetic modifications at PPARγ2 promoter in osteoporotic BMSCs. Finally, we inhibited adipogenesis and rescued osteogenesis of osteoporotic BMSCs by modulating those epigenetic modifications. Our study provides a deeper insight into the pathophysiology of osteoporosis and identifies PPARγ2 as a new target for osteoporosis therapy based on epigenetic mechanisms. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 08/2015; 1852(11). DOI:10.1016/j.bbadis.2015.08.020 · 4.66 Impact Factor
  • Yang Shen · Han Qiao · Qiming Fan · Shuhong Zhang · Tingting Tang ·
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    ABSTRACT: Microcapsules with entrapped cells hold great promise for repairing bone defects. Unfortunately, the osteoinductivity of microcapsules has been restricted by many factors, among which the deficiency of functional proteins is a significant priority. We potentiated the osteoinductivity of microencapsulated cells via cotransfection with BMP-2 and VEGF genes. Various tissue-derived mesenchymal stem cells and cell lines were compared for BMP-2 and VEGF cotransfection. Ethidium bromide (EB)/Calcein AM staining revealed that all of the cell categories could survive for 4 weeks after microencapsulation. An ELISA assay indicated that all microencapsulated BMP-2 or VEGF transfected cells could secrete gene products constitutively for 1 month. Particularly, the recombinant microencapsulated C2C12 cells released the most desirable level of BMP-2 and VEGF. Further experiments demonstrated that microencapsulated BMP-2 and VEGF cotransfected C2C12 cells generated both BMP-2 and VEGF for 4 weeks. Additionally, the cotransfection of BMP-2 and VEGF in microencapsulated C2C12 cells showed a stronger osteogenic induction against BMSCs than individual BMP-2-transfected microencapsulated C2C12 cells. These results demonstrated that the cotransfection of BMP-2 and VEGF into microencapsulated C2C12 cells is of potent utility for the potentiation of bone regeneration, which would provide a promising clinical strategy for cellular therapy in bone defects.
    BioMed Research International 01/2015; 2015(6). DOI:10.1155/2015/435253 · 2.71 Impact Factor
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    ABSTRACT: Breast cancer is one of the most common types of cancer worldwide. The majority of patients with cancer succumb to the disease as a result of distant metastases (for example, in the bones), which cause severe complications. Despite advancements in breast cancer treatment, chemotherapeutic outcomes remain far from satisfactory, prompting a search for effective natural agents with few side‑effects. Andrographolide (AP), a natural diterpenoid lactone isolated from Andrographis paniculata, inhibits cancer cell growth. The current study aimed to examine the effect of AP on breast cancer cell proliferation, survival and progression in vitro and also its inhibitory activity on breast cancer bone metastasis in vivo. To achieve this, CCK8, flow cytometry, migration, invasion, western blot, PCR and luciferase reporter assay analyses were performed in vitro as well as establishing intratibial xenograft model of breast cancer bone metastasis in vivo. The results demonstrated that AP inhibits the migration and invasion of the MBA‑MD‑231 aggressive breast cancer cell line at non‑lethal concentrations, in addition to suppressing proliferation and inducing apoptosis at high concentrations in vitro. In vivo, AP significantly inhibited the growth of tumors planted in bone and attenuated cancer‑induced osteolysis. Tartrate‑resistant acid phosphatase staining revealed osteoclast activation in tumor‑bearing mice and AP was observed to attenuate this activation. The anti‑tumor activity of AP in vitro and in vivo correlates with the downregulation of the nuclear factor κB signaling pathway and the inhibition of matrix metalloproteinase‑9 expression levels. These results indicate that AP may be an effective anti‑tumor agent for the treatment of breast cancer bone metastasis.
    Molecular Medicine Reports 11/2014; 11(2). DOI:10.3892/mmr.2014.2872 · 1.55 Impact Factor
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    ABSTRACT: Titanium (Ti) particle-induced periprosthetic osteolysis and subsequent aseptic loosening are a primary reason for total hip arthroplasty failure. The aim of this study was to assess the effect of myricetin on Ti particle-induced osteolysis and osteoclastogenesis. We demonstrated that myricetin, a natural plant extract, exerts potent inhibitory effects on Ti particle-induced osteolysis in a mouse calvarial model. Further histological analysis indicated that the inhibition of osteoclast formation and function, and the secretion of inflammatory factors, are key targets for therapeutic agents in the treatment of wear particle-induced osteolysis. In vitro, we found that myricetin suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a dose-dependent manner. Moreover, myricetin significantly reduced the expression of osteoclast-specific markers in mouse bone marrow-derived macrophages, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, the calcitonin receptor, V-ATPase d2, c-fos, and nuclear factor of activated T cells (NFAT) c1. Further investigation revealed that myricetin inhibited osteoclastogenesis through the suppression of the nuclear factor-κB (NF-κB) signaling pathway and mitogen-activated protein kinase (MAPK) pathways involving extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1/2 (JNK1/2). While, the inhibition of TNF-α and IL-1β secretion was another reason for the suppressive effect of myricetin on Ti particle-induced osteolysis. Collectively, these findings suggest that myricetin is a potential natural agent for the treatment of periprosthetic osteolysis and other osteoclast-related osteolytic diseases.
    Biochemical Pharmacology 11/2014; 93(1). DOI:10.1016/j.bcp.2014.10.019 · 5.01 Impact Factor
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    ABSTRACT: Wear particle-induced aseptic prosthetic loosening is one of the most common reasons for total joint arthroplasty (TJA). Extensive bone destruction (osteolysis) by osteoclasts plays an important role in wear particle-induced peri-implant loosening. Thus, strategies for inhibiting osteoclast function may have therapeutic benefit for prosthetic loosening. Here, we mimicked the process of magnesium (Mg) degradation in vivo and obtained Mg leach liquor (MLL) by immersing pure Mg in culture medium. For the first time, we demonstrated that MLL suppresses osteoclast formation, polarization, and osteoclast bone resorption in vitro. An in vivo assay demonstrated that MLL attenuates wear particle-induced osteolysis. Furthermore, we found that MLL significantly inhibits nuclear factor-κB (NF-κB) activation by retarding inhibitor-κB degradation and subsequent NF-κB nuclear translocation. We also found that MLL attenuates the expression of NFATc1 at both the protein and mRNA levels. These results demonstrate that MLL has anti-osteoclast activity in vitro and prevents wear particle-induced osteolysis in vivo. Collectively, our study suggests that metallic magnesium, one of the orthopedic implants with superior properties, has significant potential for the treatment of osteolysis-related diseases caused by excessive osteoclast formation and function.
    Biomaterials 08/2014; 35(24):6299–6310. DOI:10.1016/j.biomaterials.2014.04.044 · 8.56 Impact Factor
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    ABSTRACT: Wear-particle-induced osteolysis leads to prosthesis loosening, which is one of the most common causes of joint-implant failure, a problem that must be fixed using revision surgery. Thus, a potential treatment for prosthetic loosening is focused on inhibiting osteoclastic bone resorption, which prevents wear-particle-induced osteolysis. In this study, we synthesized a compound named OA-14 (N-(3- (dodecylcarbamoyl)phenyl)-1H-indole-2-carboxamide) and examined how OA-14 affects titanium (Ti)-particle-induced osteolysis and osteoclastogenesis. We report that OA-14 treatment protected against Ti-particle-induced osteolysis in a mouse calvarial model. Interestingly, the number of tartrate-resistant acid phosphatase-positive osteoclasts decreased after treatment with OA-14 in vivo, which suggested that OA-14 inhibits osteoclast formation. To test this hypothesis, we conducted in vitro studies, and our results revealed that OA-14 markedly diminished osteoclast differentiation and osteoclast-specific gene expression in a dose- and time-dependent manner. Moreover, OA-14 suppressed osteoclastic bone resorption and F-actin ring formation. Furthermore, we determined that OA-14 inhibited osteoclastogenesis by specifically blocking the p38-Mitf-c-fos-NFATc1 signaling cascade induced by RANKL (ligand of receptor activator of nuclear factor κB). Collectively, our results suggest that the compound OA-14 can be safely used for treating particle-induced peri-implant osteolysis and other diseases caused by excessive osteoclast formation and function.
    Biomaterials 07/2014; 35(32). DOI:10.1016/j.biomaterials.2014.06.055 · 8.56 Impact Factor
  • Lin Du · Qiming Fan · Bing Tu · Wei Yan · Tingting Tang ·
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    ABSTRACT: Osteosarcoma is the most common primary malignancy of bone in adolescents and young adults. There is a shortage of tumorigenic and highly metastatic human osteosarcoma cell lines that can be used for metastasis study. Here we establish and characterize a highly metastatic human osteosarcoma cell line that is derived from Saos2 cell line based on bioluminescence. The occasional pulmonary metastatic cells developed from Saos2 were isolated, harvested, characterized and named Saos2-l. The parental Saos2 and Saos2-l cells were further characterized both in vitro and in vivo. Results showed that Saos2-l cells demonstrated increased cell adhesion, migration and invasion compared to the parental Saos2 cells. Conversely, Saos2-l cells grew at a slightly slower rate than that of the parental cells. When injected into nude mice, Saos2-l cells had a greater increase in developing pulmonary metastases compared to the parental Saos2 cells. Further transcriptional profiling analysis revealed that some gene expression were up-regulated or down-regulated in the highly metastatic Saos2-l cells, indicating possible influencing factors of metastasis. Thus, we have established and characterized a highly metastatic human osteosarcoma cell line that should serve as a valuable tool for future investigations on the pathogenesis, metastasis and potential treatments of human osteosarcoma.
    International journal of clinical and experimental pathology 07/2014; 7(6):2871-82. · 1.89 Impact Factor
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    ABSTRACT: Wear particle-induced osteolysis and subsequent aseptic loosening remains the most common complication that limits the longevity of prostheses. Wear particle-induced osteoclastogenesis is known to be responsible for extensive bone erosion that leads to prosthesis failure. Thus, inhibition of osteoclastic bone resorption may serve as a therapeutic strategy for the treatment of wear particle induced osteolysis. In this study, we demonstrated for the first time that geraniin, an active natural compound derived from Geranium thunbergii, ameliorated particle-induced osteolysis in a Ti particle-induced mouse calvaria model in vivo. We also investigated the mechanism by which geraniin exerts inhibitory effects on osteoclasts. Geraniin inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, evidenced by reduced osteoclast formation and suppressed osteoclast specific gene expression. Specially, geraniin inhibited actin ring formation and bone resorption in vitro. Further molecular investigation demonstrated geraniin impaired osteoclast differentiation via the inhibition of the RANKL-induced NF-κB and ERK signaling pathways, as well as suppressed the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Collectively, our data suggested that geraniin exerts inhibitory effects on osteoclast differentiation in vitro and suppresses Ti particle-induced osteolysis in vivo. Geraniin is therefore a potential natural compound for the treatment of wear particle induced osteolysis in prostheses failure.
    Experimental Cell Research 07/2014; 330(1). DOI:10.1016/j.yexcr.2014.07.005 · 3.25 Impact Factor
  • Yugang Wang · Qiming Fan · Rui Ma · Wentao Lin · Tingting Tang ·
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    ABSTRACT: Background: Recent studies on bone have shown an endocrine role of the skeleton, which could be impaired in various human diseases, including osteoporosis, obesity, and diabetes-associated bone diseases. As a sensor and regulator of energy metabolism, AMP-activated protein kinase (AMPK) may also play an important role in the regulation of bone metabolism. The current study aimed to establish the expression profiles and phosphorylation patterns of AMPK subunits in several mesenchymal cell types. Methods: Reverse transcription-polymerase chain reaction (PCR) for relative quantification, real-time PCR for absolute quantification, and Western blotting were used to investigate the gene expression profiles and phosphorylation patterns of AMPK subunits in several mesenchymal cell types, including primary human mesenchymal stem cells (hMSCs) and hFOB, Saos-2, C3H/10T1/2, MC3T3-E1, 3T3-L1, and C2C12 cells. Results: AMPKα1 and AMPKβ1 mRNAs were abundantly expressed in all cell types. AMPKγ1 mRNA was abundantly expressed in C3H/10T1/2, MC3T3-E1, 3T3-L1, and C2C12 but not detected in human-derived cell types. AMPKγ2 mRNA was mildly expressed in all cell types. AMPKα1 protein was highly expressed in all cell types and AMPKα2 protein was highly expressed only in hFOB and Saos-2 cells. AMPKβ1 protein was abundantly expressed in all cell types except for Saos-2, in which AMPKβ2 protein overwhelmed AMPKβ1 expression. AMPKγ1 and AMPKγ2 proteins were expressed in C3H/10T1/2, MC3T3-E1, 3T3-L1, and C2C12 cells and only AMPKγ2 protein was expressed in hMSCs, hFOB and Saos-2 cells. AMPKα was phosphorylated at Thr172 and Ser485 and AMPKβ1 was phosphorylated at Ser108 and Ser182 in all cell types with a specific pattern in each cell type. Conclusion: The combination of AMPK α, β, and γ subunits and phosphorylation of AMPKα (Thr172 and Ser485) and AMPKβ1 (Ser108 and Ser182) showed a specific pattern in each cell type.
    Chinese medical journal 07/2014; 127(13):2451-7. DOI:10.3760/cma.j.issn.0366-6999.20131882 · 1.05 Impact Factor
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    ABSTRACT: The aim of this study was to assess the effect of enoxacin on osteoclastogenesis and titanium particle-induced osteolysis. Wear particles liberated from the surface of prostheses are associated with aseptic prosthetic loosening. It is well established that wear particles induce inflammation, and that extensive osteoclastogenesis plays a critical role in peri-implant osteolysis and subsequent prosthetic loosening. Therefore, inhibiting extensive osteoclast formation and bone resorption could be a potential therapeutic target to prevent prosthetic loosening. In this study, we demonstrated that enoxacin, a fluoroquinolone antibiotic, exerts potent inhibitory effects on titanium particle-induced osteolysis in a mouse calvarial model. Interestingly, the number of mature osteoclasts decreased after treatment with enoxacin in vivo, suggesting that osteoclast formation might be inhibited by enoxacin. We then performed in vitro studies to confirm our hypothesis and revealed the mechanism of action of enoxacin. Enoxacin inhibited osteoclast formation by specifically abrogating RANKL-induced JNK signaling. Collectively, these results suggest that enoxacin, an antibiotic with few side effects that is widely used in clinics, had significant potential for the treatment of particle-induced peri-implant osteolysis and other diseases caused by excessive osteoclast formation and function.
    Biomaterials 07/2014; 35(22):5721–5730. DOI:10.1016/j.biomaterials.2014.04.006 · 8.56 Impact Factor
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    ABSTRACT: Bone is a major site of metastasis for several types of malignant tumor. Specific interactions between tumor cells and the bone microenvironment contribute to the tendency of tumors to metastasize to bone. Furthermore, Wnt5a participates in the progression of several types of malignant tumor. This study investigates the role of Wnt5a in the migration of the prostate cancer (PCa) cell line PC3 toward bone marrow stromal cell (BMSC)‑conditioned medium (CM). The expression of 22 genes associated with bone metastasis was measured in three PCa cell lines (LNCaP, PC3 and DU145). Subsequently, the proliferation and migration capacities of PC3 cells treated either with small interfering RNA (siRNA) against Wnt5a or with recombinant mouse (rm) Wnt5a were analyzed with alamarBlue and transwell assays. BMSC‑CM was collected to evaluate its effect on PC3 cell migration. Also, the expression of Wnt5a in BMSCs was knocked down prior to collection of the CM to evaluate its effects on the migration of PC3 cells. Significantly higher levels of Wnt5a mRNA expression were identified in the PC3 cells, compared with those in LNCaP and DU145 cells. Silencing Wnt5a expression with siRNA reduced the migration capacity of PC3 cells by 50%. The addition of rmWnt5a improved the migration capacity of PC3 cells in a concentration‑dependent manner. PC3 cells preferred to migrate toward BMSC‑CM than toward the control. CM from Wnt5a siRNA‑treated BMSCs significantly reduced PC3 cell migration. Wnt5a promotes PC3 cell migration toward BMSC‑CM, indicating that Wnt5a is a potential therapeutic target for the treatment of advanced PCa.
    Molecular Medicine Reports 09/2013; 8(5). DOI:10.3892/mmr.2013.1698 · 1.55 Impact Factor
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    ABSTRACT: Bone defects are common in elderly patients suffering from osteoporosis. Current methods of bone defect treatment for osteoporosis are not always satisfactory. In this study, we demonstrated that bone marrow mesenchymal stem cells (MSCs) harvested from goats with long-term estrogen deficiencies exhibited a lower proliferation rate and decreased osteogenic capacity, which are critical obstacles for bone defect repair in the elderly. However, by combining autologous enriched bone marrow mesenchymal stem cells with porous β-TCP, we successfully repaired critical-sized bone defects in the medial femoral condyle of the osteoporotic goats. Both micro-CT images and histomorphometry analysis illustrated improved bone formation following the enriched MSC therapy. Thus, we proposed autologous enriched bone marrow mesenchymal stem cells as a quick, safe therapeutic strategy to treat osteoporotic bone defects.
    Biomaterials 04/2012; 33(20):5076-84. DOI:10.1016/j.biomaterials.2012.03.069 · 8.56 Impact Factor
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    ABSTRACT: Although Sox9 is essential for chondrogenic differentiation and matrix production, its application in cartilage tissue engineering has been rarely reported. In this study, the chondrogenic effect of Sox9 on bone marrow mesenchymal stem cells (BMSCs) in vitro and its application in articular cartilage repair in vivo were evaluated. Rabbit BMSCs were transduced with adenoviral vector containing Sox9. Toluidine blue, safranin O staining and real-time PCR were performed to check chondrogenic differentiation. The results showed that Sox9 could induce chondrogenesis of BMSCs both in monolayer and on PGA scaffold effectively. The rabbit model with full-thickness cartilage defects was established and then repaired by PGA scaffold and rabbit BMSCs with or without Sox9 transduction. HE, safranin O staining and immunohistochemistry were used to assess the repair of defects by the complex. Better repair, including more newly-formed cartilage tissue and hyaline cartilage-specific extracellular matrix and greater expression of several chondrogenesis marker genes were observed in PGA scaffold and BMSCs with Sox9 transduction, compared to that without transduction. Our findings defined the important role of Sox9 in the repair of cartilage defects in vivo and provided evidence that Sox9 had the potential and advantage in the application of tissue engineering.
    Biomaterials 03/2011; 32(16):3910-20. DOI:10.1016/j.biomaterials.2011.02.014 · 8.56 Impact Factor
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    ABSTRACT: Bone-like fluoridated hydroxyapatite (FHA) coatings were prepared on Mg-6 wt.%Zn substrates using electrochemical method. Human bone marrow stromal cells (hBMSCs) were utilized to investigate the cellular biocompatibility of Mg-6 wt.%Zn alloy after surface modification. The adhesion of hBMSCs was evaluated using scanning electron microscopy (SEM) and laser scanning confocal microscopy (LSCM). The proliferation of the cells was also measured by carrying out the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. And the alkaline phosphatase activity (ALP) was assessed to evaluate the early stage of differentiation. Lastly, reverse transcription-polymerase chain reaction (RT-PCR) test was taken. It was found that the hBMSCs displayed better cell functions on the bioactive FHA coated alloy, compared to the bare Mg-6 wt.%Zn alloy. The in vitro results indicated that the bioactive FHA coating can improve the interfacial bioactivity of Mg-6 wt.%Zn substrate, specifically, both on biodegradation behavior control and good cellular proliferation and differentiation.
    Biomaterials 08/2010; 31(22):5782-8. DOI:10.1016/j.biomaterials.2010.04.023 · 8.56 Impact Factor
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    Qiming Fan · Tingting Tang · Xiaoling Zhang · Kerong Dai ·
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    ABSTRACT: The balance between osteogenesis and adipogenesis of mesenchymal stem cells is disrupted in various human diseases. Investigating the mechanisms that fine-tune this balance is of medical importance. Identification of potential target gene which can be used to study the relationship between them could be really helpful for this purpose. In the current study, we used C3H10T1/2 as model cells and through which two models of both osteogenesis induced by bone-morphogenetic protein (BMP)-2 and transdifferentiation from osteogenesis to adipogenesis were established. We investigated the role of CCAAT/enhancer binding protein (C/EBP)-alpha in these two systems. Then from epigenetic point of view, we elucidated the underlying molecular mechanisms preliminarily. The results showed that down-regulations of both C/EBP-alpha expression and its inducibility in response to insulin, fetal bovine serum, methylisobutylxanthine and dexamethasone (IFMD) adipogenic hormonal cocktail were observed in terminal stage of osteogenesis of C3H10T1/2 cells induced by BMP-2. And overexpression of C/EBP-alpha could lead to inhibition of osteogenesis differentiation and rescue attenuation of potential of adipogenic conversion in this process. Furthermore, we provided evidence that remarkable DNA hypermethylation and histones 3 and 4 hypoacetylation in -1286 bp/1065 bp promoter region of C/EBP-alpha were involved in both of down-regulations. Our data suggest that C/EBP-alpha functions as regulator in the balance between osteogenesis and adipogenesis of C3H10T1/2 cells and may be a therapeutic target.
    Journal of Cellular and Molecular Medicine 08/2009; 13(8B):2489-505. DOI:10.1111/j.1582-4934.2008.00606.x · 4.01 Impact Factor

Publication Stats

168 Citations
77.03 Total Impact Points


  • 2014
    • Renji Hospital
      Shanghai, Shanghai Shi, China
  • 2010-2014
    • Shanghai Jiao Tong University
      • Department of Orthopaedics
      Shanghai, Shanghai Shi, China
  • 2009
    • Shanghai Institutes for Biological Sciences
      • Institute of Health Sciences
      Shanghai, Shanghai Shi, China