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Huang L.,Zhejiang Chinese Medical University | Pan J.,Zhejiang Chinese Medical University | Jin H.,Zhejiang Chinese Medical University | Jin H.,Institute of Orthopaedics and Traumatology of Zhejiang Province | And 5 more authors.
Journal of Clinical Densitometry | Year: 2015

Quantitative ultrasound (QUS) assessment of bone health status, as a reliable method, is rapidly gaining popularity. Speed of sound (SOS) is one parameter of skeletal status provided by QUS assessment. The objective of the present study was first to determine the normative distal radius SOS data on healthy Chinese mainland men and women and second to investigate the effects of sex, age, and body size on this parameter. A study cohort consisting of 19,980 healthy Chinese women and 8722 men aged 20-89yr participated in this investigation. They answered a detailed questionnaire on their healthy condition, and their anthropometric measurements were taken. Their distal radius SOS values were evaluated using the Sunlight ultrasound systems. The distal radius SOS values exhibited a characteristic rise-then-fall pattern with increasing age in both sexes. The peak SOS value occurred at the age of 40-49 both in males and females. Age-related differences were both pronounced among males and females. Pearson correlation and regression analysis showed that age was a major determinant of SOS in both sexes. In females, SOS values had a much stronger correlation with age than male subjects. Body weight was also correlated with SOS but not as well as age. The SOS values of distal radius at present study may be used as normal reference data for Chinese mainland population and will be useful for comparing the results of individual studies and determining diagnostic criteria of osteoporosis by QUS. © 2015 The International Society for Clinical Densitometry.


Mao Q.,Zhejiang Chinese Medical University | Wang W.,Zhejiang Chinese Medical University | Xu T.,Zhejiang Chinese Medical University | Xu T.,Institute of Orthopaedics and Traumatology of Zhejiang Province | And 8 more authors.
Journal of Bone and Mineral Research | Year: 2015

The objective of this study was to determine the benefits of combination treatment with mechanical support and targeted intra-arterial infusion of peripheral blood stem cells (PBSCs) mobilized by granulocyte-colony stimulating factor (G-CSF) via the medial circumflex femoral artery on the progression of osteonecrosis of the femoral head (ONFH). Fifty-five patients (89 hips) with early and intermediate stage ONFH were recruited and randomly assigned to combination treatment or mechanical support treatment (control group). All hips received mechanical support treatment (porous tantalum rod implantation). Then, hips in the combination treatment group were performed targeted intra-arterial infusion of PBSCs. At each follow-up, Harris hip score (HHS) and Association Research Circulation Osseous (ARCO) classification were used to evaluate the symptoms and progression of osteonecrosis. Total hip arthroplasty (THA) was assessed as an endpoint at each follow-up. At 36 months, 9 of the 41 hips (21.95%) in the control group progressed to clinical failure and underwent THA whereas only 3 of the 48 hips (6.25%) in the combination treatment group required THA (p = 0.031). Kaplan-Meier survival analysis showed a significant difference in the survival time between the two groups (log-rank test; p = 0.025). Compared to the control group, combination treatment significantly improved the HHS at 36 months (p = 0.003). At the final follow-up examination, radiological progression was noted in 13 of 41 hips (31.71%) for the control group, but in only 4 of 48 hips (8.33%) for the combination treatment group (p = 0.005). The overall collapse rates were 15.15% (5/33 hips) and 8.11% (3/37 hips) in the control and combination treatment groups, respectively. Targeted intra-arterial infusion of PBSCs is capable of enhancing the efficacy of biomechanical support in the treatment of ONFH. This clinical trial confirmed that the combination treatment might be a safe and feasible choice for the treatment of early or intermediate stages of ONFH. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.


Mao Q.,Zhejiang Chinese Medical University | Mao Q.,Institute of Orthopaedics and Traumatology of Zhejiang Province | Jin H.,Zhejiang Chinese Medical University | Jin H.,Institute of Orthopaedics and Traumatology of Zhejiang Province | And 6 more authors.
Bone | Year: 2013

Objective: To investigate the efficacy and safety of targeted delivery of autologous bone marrow mononuclear cells (BMMCs), which are highly enriched with mesenchymal stem cells (BMMSCs), via medial circumflex femoral artery in the treatment of osteonecrosis of the femoral head (ONFH). Methods: 62 patients (78 hips) with ONFH were recruited in this study. All of these patients were treated with BMMCs perfusion via medial circumflex femoral artery. The concentrated BMMCs (30-60. ml) were gained from autologous bone marrow (100-200. ml) harvested from anterior iliac crest and then were intra-arterially perfused into the femoral head. Ficat stage was used to classify the radiological stage of ONFH. Harris hip score was used to evaluate the clinical symptoms of osteonecrosis. Ficat stage and Harris hip scores were assessed at onset of treatment at 6, 12, 24, 36, 48 and 60. months after the initial treatment. Total hip arthroplasty (THA) was also assessed as an endpoint at each follow-up. Results: A follow-up on the patient was done at the end of five years, and 92.31% (72 of 78) of hips achieved a satisfactory clinical result while only 6 hips (7.69%) progressed to clinical failure and required THA. Radiological progression was noted in 34 of 78 hips (43.59%); the overall rate of collapse was 38.24% (26 of 68 hips) in stage-I and stage-II hip combinations and 12.5% (2 of 16) in stage-I hips and 46.15% (24 of 52) in stage-II hips. The mean time of conversion to THA was 3. years (1 to 5. years) and the average time to collapse were 3.5. years (1-5. years). The mean Harris hip score increased from 59 points at baseline to 75 points at 12. months, 82 points at 24. months, 81 points at 36. months, 79 points at 48. months and 74 points at 60. months. Five years after the treatment, 3 of 10 hips (30%) in stage-III had deteriorated to clinical failure whereas only 3 of 68 hips (4.41%) in stage-I and II combination had progressed to clinical failure (p. <. 0.05). Kaplan-Meier survival analysis showed a significant difference in the time to failure between the pre-collapse hips (Ficat stage-I and II) and the post-collapse hips (Ficat stage-III) at five years follow-up (Log-rank test; p. <. 0.01). No complication was found in any patients. Conclusions: Autologous BMMSC perfusion via the medial circumflex femoral artery can relieve symptoms, improve hip function and delay the progression of ONFH. The clinical outcome is better when it is applied prior to the collapse. This work demonstrates that autologous BMMSC perfusion via the medial circumflex femoral artery is a safe, effective and minimally invasive treatment strategy for early-stage ONFH. © 2013 Elsevier Inc.


Huang Z.,Zhejiang Chinese Medical University | Huang Z.,Institute of Orthopaedics and Traumatology of Zhejiang Province | Li J.,Zhejiang Chinese Medical University | Du S.,Zhejiang University | And 6 more authors.
Oncotarget | Year: 2016

The FK506-binding protein 14 (FKBP14) is a subfamily of immunophilins, has been implicated in various biochemical processes. However, its effects on the primary malignant bone tumor, osteosarcoma, are unclear. Here, we reported that FKBP14 may be an oncogene as it overexpressed in osteosarcoma tissues and cell lines, and FKBP14 expression was correlated with metastases, recurrence, tumor maximum diameter and poor survival time. FKBP14 was associated with the biological pathways including cell cycle, apoptosis and metastasis. Furthermore, we detected FKBP14 knockdown induced cell cycle arrest, apoptosis, invasion and adhesion in vitro. FKBP14 knockdown decreased the protein levels of PCNA, CDK1 and CCNB1 that promotes cell cycle, increased Bax, caspase-3 and caspase-7 protein involved in promoting cell apoptosis, and increased KIF4A expression as well as decreased SMC4 and TMEM33 proteins that contribute to cell invasion and adhesion. In addition, FKBP14 knockdown also caused a significant inhibition in tumor growth in vivo. Then, we found that the protein RhoA was identified as a binding partner of FKBP14. Taken together, FKBP14 may act as an oncogene in osteosarcoma via suppressing apoptosis and promoting invasion and adhesion in osteosarcoma carcinogenesis. FKBP14 may be a prognostic factor and potential target for osteosarcoma treatment.


Huang Z.,Xiaoshan Chinese Medical Hospital | Huang Z.,Zhejiang Chinese Medical University | Huang Z.,Institute of Orthopaedics and Traumatology of Zhejiang Province | Li J.,Xiaoshan Chinese Medical Hospital | And 9 more authors.
PLoS ONE | Year: 2016

Reactive oxygen species (ROS)-induced chondrocytes apoptosis plays a key role in osteoarthritis (OA) pathogenesis. Uncoupling protein 4 (UCP4) can protect cells against oxidative stress via reducing ROS production and cell apoptosis. Here, silencing of UCP4 in primary chondrocytes significantly inhibited cell survival, but induced ROS production and cell apoptosis. UCP4 mRNA of cartilage tissues was decreased in osteoarthritis patients, which was negatively correlated with synovial fluid (SF) leptin concentration. Moreover, leptin treatment (5, 10 and 20 ng/ml) of primary cultured chondrocytes significantly decreased mRNA and protein levels of UCP4, but increased ROS production and cell apoptosis in a dose-dependent manner. The effects of leptin treatment (20 ng/ml) on chondrocytes was partially reversed by ectopic expression of UCP4. More importantly, intraarticularly injection of UCP4 adenovirus remarkably alleviate OA progression and cell apoptosis in a rat OA model induced by anterior cruciate ligament transection (ACLT). In conclusion, UCP4, whose expression was suppressed by leptin, may be involved in the ROS production and apoptosis of chondrocytes, thus contributing to the OA pathogenesis. © 2016 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Zhang S.,Zhejiang Chinese Medical University | Zhang S.,Institute of Orthopaedics and Traumatology of Zhejiang Province | Zhang S.,Rush University Medical Center | Lu C.,Zhejiang Chinese Medical University | And 8 more authors.
Haemophilia | Year: 2015

Introduction: Focal bone destruction has a high prevalence in haemophilic arthropathy (HA) affected joints, but the mechanism remains unclear. Aim: We undertook this study on clinic samples to explore the focal bone destruction in femoral heads suffered with end-stage HA. Methods: Twenty-one femoral heads from HA patients and 19 femoral heads from rheumatoid arthritis (RA) patients were scanned by micro-CT. Histological analysis, including TRAP staining of subchondral bone were performed to evaluate the bone destruction and osteoclasts activity. RANKL, OPG as well as pro-inflammatory cytokines, such as TNF-α and IL-1β in subchondral bone were detected by immunohistochemistry (IHC) method. Results: Severe focal lesion was observed in all the HA and RA femoral heads by micro-CT imaging and histological analysis. The mean percentage of lesion volume to total volume of the femoral heads from HA patients was significantly higher than those from RA patients. There was no significant difference in osteoclasts numbers in subchondral bone between HA and RA groups. By IHC analysis, high expression of RANKL, TNF-α, IL-1β and low expression of OPG and RANK were observed in subchondral bone, and there were no significant differences in the expression of RANKL, OPG, RANK, TNF-α and IL-1β in femoral heads derived from HA and RA patients. Conclusion: Our findings demonstrated the focal bone destruction coupled with inflammatory osteoclastogenesis at subchondral bone in femoral heads from patients with end-stage HA, and that was similar to the changes in the femoral heads of RA patients. © 2015 John Wiley & Sons Ltd.


Huang Z.M.,Xiaoshan Chinese Medical Hospital | Huang Z.M.,Zhejiang Chinese Medical University | Huang Z.M.,Institute of Orthopaedics and Traumatology of Zhejiang Province | Du S.H.,Zhejiang University | And 6 more authors.
Osteoarthritis and Cartilage | Year: 2016

Objective: Leptin has been found highly expressed in human osteoarthritis. We aimed to explore the possible effects and mechanisms of leptin on the apoptosis and autophagy of chondrocytes during osteoarthritis pathogenesis. Methods: Gene expression profile from osteoarthritis affected and preserved cartilage were downloaded from NCBI's Gene Expression Omnibus database (GSE57218). Lysyl oxidase-like 3 (LOXL3) mRNA expression in cartilage tissues and leptin concentration in joint synovial fluid (SF) was measured in samples from 45 osteoarthritis patients and 25 healthy donors by real-time PCR and radioimmunoassay, respectively. Rat osteoarthritis model was induced by anterior cruciate ligament transection (ACLT). The expression of apoptosis regulators and autophagy markers were detected by Western blot. Cell survival and cell apoptosis were identified by CCK-8 and flow cytometry, respectively. Results: Re-analysis on GSE57218 indicated that LOXL3 mRNA was upregulated in osteoarthritis affected cartilage. LOXL3 mRNA was upregulated in osteoarthritis patients, which was positively correlated with SF leptin concentration. Similar results were obtained in rat osteoarthritis model. Moreover, ACLT surgery led to a significant increase in the protein levels of cleaved caspase 3, and a notable decrease in the protein levels of Bcl-2, LC3 II/LC3 I and Beclin1. Silencing of LOXL3 in ACLT and leptin treated primary chondrocytes significantly inhibited cell apoptosis, and promoted cell proliferation and autophagy. Moreover, overexpression of LOXL3 remarkably inhibited autophagy of chondrocytes via activating mTORC1. Conclusions: LOXL3, a downstream of leptin, stimulated the apoptosis, but inhibited the autophagy of chondrocytes. LOXL3 is a potential therapy target for osteoarthritis. © 2016 Osteoarthritis Research Society International.


Chen G.,Fudan University | Chen G.,Zhejiang University | Fang T.,Fudan University | Qi Y.,Zhejiang University | And 9 more authors.
Cell Transplantation | Year: 2016

Bone nonunion treatments pose a challenge in orthopedics. This study investigated the joint effects of using mesenchymal stem cell (MSC) sheets with local injection of stromal cell-derived factor-1 (SDF-1) on bone formation. In vitro, we found that migration of MSCs was mediated by SDF-1 in a dose-dependent manner. Moreover, stimulation with SDF-1 had no direct effect on the proliferation or osteogenic differentiation of MSCs. Furthermore, the results indicated elevated expression levels of bone morphogenetic protein 2, alkaline phosphatase, osteocalcin, and vascular endothelial growth factor in MSC sheets compared with MSCs cultured in medium. New bone formation in fractures was evaluated by X-ray, micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, Safranin-O staining, and immunohistochemistry in vivo. In the rat bone fracture model, the MSC sheets transplanted into the injured site along with injection of SDF-1 showed significantly more new bone formation within the gap. Moreover, at 8 weeks, complete bone union was obtained in this group. In contrast, the control group showed nonunion of the bone. Our study suggests a new strategy involving the use of MSC sheets with a local injection of SDF-1 for hard tissue reconstruction, such as the healing of nonunions and bone defects. © 2016 Cognizant, LLC.


Jin H.,Zhejiang Chinese Medical University | Jin H.,Institute of Orthopaedics and Traumatology of Zhejiang Province | Xu T.,Zhejiang Chinese Medical University | Xu T.,Institute of Orthopaedics and Traumatology of Zhejiang Province | And 12 more authors.
Stem Cells International | Year: 2016

This study aimed to investigate if autologous bone marrow mesenchymal stem cells (MSCs) could treat osteonecrosis of the femoral head (ONFH) and what the fate and distribution of the cells are in dogs. Twelve Beagle dogs were randomly divided into two groups: MSCs group and SHAM operated group. After three weeks, dogs in MSCs group and SHAM operated group were intra-arterially injected with autologous MSCs and 0.9% normal saline, respectively. Eight weeks after treatment, the necrotic volume of the femoral heads was significantly reduced in MSCs group. Moreover, the trabecular bone volume was increased and the empty lacunae rate was decreased in MSCs group. In addition, the BrdU-positive MSCs were unevenly distributed in femoral heads and various vital organs. But no obvious abnormalities were observed. Furthermore, most of BrdU-positive MSCs in necrotic region expressed osteocalcin in MSCs group and a few expressed peroxisome proliferator-activated receptor-γ (PPAR-γ). Taken together, these data indicated that intra-arterially infused MSCs could migrate into the necrotic field of femoral heads and differentiate into osteoblasts, thus improving the necrosis of femoral heads. It suggests that intra-arterial infusion of autologous MSCs might be a feasible and relatively safe method for the treatment of femoral head necrosis. © 2016 Hongting Jin et al.


PubMed | Institute of Orthopaedics and Traumatology of Zhejiang Province, Rush University Medical Center and Zhejiang Chinese Medical University
Type: Journal Article | Journal: Haemophilia : the official journal of the World Federation of Hemophilia | Year: 2015

Focal bone destruction has a high prevalence in haemophilic arthropathy (HA) affected joints, but the mechanism remains unclear.We undertook this study on clinic samples to explore the focal bone destruction in femoral heads suffered with end-stage HA.Twenty-one femoral heads from HA patients and 19 femoral heads from rheumatoid arthritis (RA) patients were scanned by micro-CT. Histological analysis, including TRAP staining of subchondral bone were performed to evaluate the bone destruction and osteoclasts activity. RANKL, OPG as well as pro-inflammatory cytokines, such as TNF- and IL-1 in subchondral bone were detected by immunohistochemistry (IHC) method.Severe focal lesion was observed in all the HA and RA femoral heads by micro-CT imaging and histological analysis. The mean percentage of lesion volume to total volume of the femoral heads from HA patients was significantly higher than those from RA patients. There was no significant difference in osteoclasts numbers in subchondral bone between HA and RA groups. By IHC analysis, high expression of RANKL, TNF-, IL-1 and low expression of OPG and RANK were observed in subchondral bone, and there were no significant differences in the expression of RANKL, OPG, RANK, TNF- and IL-1 in femoral heads derived from HA and RA patients.Our findings demonstrated the focal bone destruction coupled with inflammatory osteoclastogenesis at subchondral bone in femoral heads from patients with end-stage HA, and that was similar to the changes in the femoral heads of RA patients.

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