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1.  Intra-articular injection of synthetic microRNA-210 accelerates avascular meniscal healing in rat medial meniscal injured model 
Introduction
The important functions of the meniscus are shock absorption, passive stabilization and load transmission of the knee. Because of the avascularity of two-thirds of the meniscal center region, the treatment of tears in this area is hard. Recently, microRNAs have been proven to play an important role in the pathogenesis of diseases. We focused on microRNA (miR)-210, which plays a wide spectrum of roles comprising mitochondrial metabolism, angiogenesis, DNA repair and cell survival. This study aimed to investigate the effect of intra-articular injection of synthetic miR-210 on the injured meniscus in the avascular zone.
Methods
The middle segments of the medial meniscus of Spraque Dawley rats were incised longitudinally with a scalpel. An intra-articular injection of double-stranded (ds) miR-210 (for control group using control dsRNA) with atelocollagen was administered immediately after injury. Four weeks and 12 weeks after the injection, we conducted a histologic evaluation, immunohistochemical evaluation and Real-time PCR analysis. In vitro, the inner meniscus and synovial cells were isolated from rat knee joint, and were transfected with ds miR-210 or control dsRNA. Real-time PCR and immunohistochemical evaluations were performed.
Results
Twenty-four hours after the injection, FAM (Fluorescein amidite) labeled miR-210 was observed in the cells around the injured site. Four weeks after the injection, the injured site of the miR-210 group was filled with repaired tissue while that of the control was not repaired. In gene expression analysis of the meniscus, the expression of miR-210, Collagen type 2 alpha 1 (Col2a1), Vascular endothelial growth factor (VEGF), and Fibroblast growth factor-2 (FGF2) in the miR-210 group was significantly higher than that in the control. At 12 weeks, the intra-articular injection of miR-210 had healed the injured site of the meniscus and had prevented articular cartilage degeneration. In vitro, miR-210 upregulated Col2a1 expression in the meniscus cells and VEGF and FGF2 expression in the synovial cells.
Conclusions
An intra-articular injection of ds miR-210 was effective in the healing of the damaged white zone meniscus through promotion of the collagen type 2 production from meniscus cells and through upregulated of VEGF and FGF2 from synovial cells.
doi:10.1186/s13075-014-0488-y
PMCID: PMC4265493  PMID: 25430980
2.  Bony impingement depends on the bone morphology of the hip after total hip arthroplasty 
International Orthopaedics  2013;37(10):1897-1903.
Purpose
The purpose of this study was to evaluate whether the bone morphology of the hip affects the range of motion (ROM) in total hip arthroplasty (THA).
Methods
Using the CT data of 63 patients who underwent THA, we calculated the ROM of flexion (Flex), internal rotation (Int-R) and external rotation (Ext-R) using 3D dynamic analysis software. We measured the distance between the anterior surface of the stem and anterior aspect of the greater trochanter (GTa length) at the cutting point and between the tip of the antero-inferior iliac spine (AIIS) and coronal plane of both femoral heads (AIIS length), as a parameter of the femur and pelvis, respectively. The relationship between the ROM, bone anatomy and impingement site was evaluated.
Results
We found a significant decrease in the ROM of Flex and the Int-R to be inversely proportional to the GTa and AIIS length. In Flex and Int-R, the anterior intertrochanteric region often impinges on the AIIS in patients with larger bone anatomy.
Conclusions
We demonstrated that the bone morphology of the hip substantially affects the ROM of Flex and Int-R, especially in patients with large bone anatomy. For these patients we should consider bony impingement in THA.
doi:10.1007/s00264-013-1979-1
PMCID: PMC3779569  PMID: 23860789
3.  Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes 
Arthritis Research & Therapy  2014;16(4):R163.
Introduction
Osteoarthritis (OA) is a whole joint disease, and characterized by progressive degradation of articular cartilage, synovial hyperplasia, bone remodeling and angiogenesis in various joint tissues. Exosomes are a type of microvesicles (MVs) that may play a role in tissue-tissue and cell-cell communication in homeostasis and diseases. We hypothesized that exosomes function in a novel regulatory network that contributes to OA pathogenesis and examined the function of exosomes in communication among joint tissue cells.
Methods
Human synovial fibroblasts (SFB) and articular chondrocytes were obtained from normal knee joints. Exosomes isolated from conditioned medium of SFB were analyzed for size, numbers, markers and function. Normal articular chondrocytes were treated with exosomes from SFB, and Interleukin-1β (IL-1β) stimulated SFB. OA-related genes expression was quantified using real-time PCR. To analyze exosome effects on cartilage tissue, we performed glycosaminoglycan release assay. Angiogenic activity of these exosomes was tested in migration and tube formation assays. Cytokines and miRNAs in exosomes were analyzed by Bio-Plex multiplex assay and NanoString analysis.
Results
Exosomes from IL-1β stimulated SFB significantly up-regulated MMP-13 and ADAMTS-5 expression in articular chondrocytes, and down-regulated COL2A1 and ACAN compared with SFB derived exosomes. Migration and tube formation activity were significantly higher in human umbilical vein endothelial cells (HUVECs) treated with the exosomes from IL-1β stimulated SFB, which also induced significantly more proteoglycan release from cartilage explants. Inflammatory cytokines, IL-6, MMP-3 and VEGF in exosomes were only detectable at low level. IL-1β, TNFα MMP-9 and MMP-13 were not detectable in exosomes. NanoString analysis showed that levels of 50 miRNAs were differentially expressed in exosomes from IL-1β stimulated SFB compared to non-stimulated SFB.
Conclusions
Exosomes from IL-1β stimulated SFB induce OA-like changes both in vitro and in ex vivo models. Exosomes represent a novel mechanism by which pathogenic signals are communicated among different cell types in OA-affected joints.
doi:10.1186/ar4679
PMCID: PMC4261911  PMID: 25092378
4.  Magnetic Targeting of Human Peripheral Blood CD133+ Cells for Skeletal Muscle Regeneration 
Skeletal muscle injuries often leave lasting functional damage or pain. Muscle injuries are routinely treated conservatively, but the most effective treatment to promote the repair of injured muscles has not yet been established. Our previous report demonstrated that human peripheral blood-derived CD133+ cell transplantation to rat skeletal muscle injury models inhibited fibrosis and enhanced myogenesis after injury. However, the acquisition of a sufficient number of cells remains the limitation for clinical application, as the CD133+ population is rare in human blood. In this study, we applied a magnetic cell targeting system to accumulate transplanted cells in the muscle injury site and to enhance the regenerative effects of CD133+ cell transplantation, focusing on the fact that CD133+ cells are labeled with a magnetic bead for isolation. For the magnetic cell targeting, the magnet field generator was set up to adjust the peak of the magnetic gradient to the injury site of the tibialis anterior muscle, and 1×104 human peripheral blood CD133+ cells were locally injected into the injury site. This cell number is 10% of that used in the previous study. In another group, the same number of CD133+ cells was injected without magnetic force. The CD133+ cells transplanted with the magnetic force were more accumulated in the muscle injury site compared with the CD133+ cells transplanted without the magnetic force. In addition, the transplantation of CD133+ cells under the magnetic control inhibited fibrous scar formation and promoted angiogenesis and myogenesis, and also upregulated the mRNA expression of myogenic transcription factors, including Pax7, MyoD1 and Myogenin. However, the transplantation of CD133+ cells without the magnetic force failed to demonstrate these effects. Thus, our magnetic cell targeting system enables transplantation of a limited number of CD133+ cells to promote the repair of skeletal muscle injury.
doi:10.1089/ten.tec.2012.0431
PMCID: PMC3689931  PMID: 23298291
5.  Regenerative medicine in orthopedics using cells, scaffold, and microRNA 
Journal of Orthopaedic Science  2014;19(4):521-528.
Cells, scaffold, and growth factors are crucially important in regenerative medicine and tissue engineering. Progress in science and technology has enabled development of these three factors, with basic research being applied clinically. In the past decade, we have investigated tissue regeneration in animal models of musculoskeletal disorders by using cells, scaffold, and delivery systems which has been relatively easy to apply and develop in clinical settings. Moreover, microRNA (miRNA), which are important in biological processes and in the pathogenesis of human diseases, have been used in research on regenerative medicine. For the cell source, we focused on mesenchymal stem cells (MSC) and CD34+ and CD133+ cells as endothelial progenitor cells for regeneration of musculoskeletal organs. These cells are accessible and safe. For less invasive and more effective therapy, we developed a novel cell-delivery system using magnetic force to accumulate cells at a desired site. Furthermore, administration of synthetic miRNA could enhance tissue regeneration. In our studies, use of these cells combined with a cell-delivery system, miRNA, scaffold, and cytokines has led to effective regeneration of musculoskeletal tissues including cartilage, bone, ligaments, muscle, peripheral nerves, and spinal cord. The current and future objective is more effective and less invasive cell-based therapy with spatial control of transplanted cells by use of an external magnetic force. Analysis of efficiency, safety, and the mechanism of tissue regeneration by cells, scaffold, and miRNA will lead to more promising regenerative medicine, involving the development of a new generation of therapy. This review will focus on our regenerative medicine research, which focuses on clinical application of cells, scaffold, and miRNA.
doi:10.1007/s00776-014-0575-6
PMCID: PMC4111855  PMID: 24819307
6.  An Augmentation Suture Technique for Arthroscopic Rotator Cuff Repair 
Arthroscopy Techniques  2014;3(3):e313-e315.
The double-row suture technique and the suture-bridge technique have been used for rotator cuff repair to decrease the occurrence of retears. However, when only the degenerated tendon end is sutured, the risk of retear remains. The augmentation suture technique is a new procedure that connects the intact medial tendon to the lateral greater tuberosity, and this approach may protect the initial repair site. The procedures for this technique are as follows: 2 sutures are placed through the medial intact tendon, the cuff tear is repaired by the single-row technique, 2 sutures are pulled laterally over the single-row repair site, and 2 sutures are fixed at the lateral greater tuberosity with a push-in–type anchor. This technique is simple and easy and does not require special equipment. Moreover, this approach can augment the single-row repair technique without creating high tension at the cuff end.
doi:10.1016/j.eats.2014.01.011
PMCID: PMC4129987  PMID: 25126493
7.  T2 Mapping Magnetic Resonance Imaging Encourages an Arthroscopic Approach for Osteoid Osteoma in the Acetabulum 
Arthroscopy Techniques  2014;3(2):e251-e254.
Intra-articular osteoid osteoma (OO) is uncommon, especially in the hip joint. Delayed treatment may cause early osteoarthritis; however, diagnosis and complete excision are often challenging. We describe the feasibility of the combination of T2 mapping magnetic resonance imaging evaluation and arthroscopic excision of OO in the acetabulum. A 12-year-old boy presented with a 6-month history of hip pain. An undifferentiated tumor of the medial wall of the acetabulum was suspected on radiographs and computed tomography. T2 mapping showed joint effusion, and the T2 value of the acetabular cartilage just above the tumor was significantly high. These findings suggested OO in the acetabulum. An arthroscopic excision was performed for biopsy and excision of the tumor to avoid damage to the normal cartilage and growth plate. Histologic examination confirmed the OO. At 16 months' follow-up, there was no evidence of recurrence. This is the first report to evaluate intra-articular OO by T2 mapping and to treat it arthroscopically. Arthroscopic treatment assisted by T2 mapping has excellent potential as a minimally invasive technique to enable us to approach the tumor from the area of discriminative abnormal cartilage with minimal damage to the normal cartilage and surrounding tissue.
doi:10.1016/j.eats.2013.11.006
PMCID: PMC4044503  PMID: 24904771
8.  Ten year results of transtrochanteric valgus osteotomy with or without the shelf procedure 
International Orthopaedics  2013;37(4):599-604.
Purpose
The purpose of this study was to examine retrospectively the effectiveness of Sugioka’s transtrochanteric valgus osteotomy (TVO) combined with the shelf procedure for patients who had advanced osteoarthritis (OA) of the hip with severe acetabular dysplasia.
Methods
Sixty-two hips in 61 patients were reviewed retrospectively between April 1993 and March 2009. Of these hips, 25 hips with the pre-operative acetabular head index (AHI) ≥ 60 % (single group) underwent a TVO, whereas the other 37 with AHI < 60 % (combined group) underwent a TVO combined with the shelf procedure.
Results
Using conversion to total hip arthroplasty as the endpoint, the Kaplan-Meier survival rates at ten years were calculated to be 85.5 % for the single group and 100 % for the combined group; there was a significant difference between the two groups (p < 0.05, log-rank test). Similarly, calculated using progressive OA as the endpoint, survival rates at ten years were 69.5 % and 89.3 % respectively; there was also a significant difference between the two groups (p < 0.05, log-rank test). In the single group, the latest radiographic evaluations of the patients with the pre-operative AHI ≥ 70 % were significantly better than those of the patients with the pre-operative AHI < 70 % (P < 0.05).
Conclusion
More satisfactory ten year results of TVO were obtained in cases that had a pre-operative AHI of ≥70 %, or where the shelf procedure was added. It is desirable that acetabuloplasty be added for patients with pre-operative AHI < 70 %.
doi:10.1007/s00264-013-1810-z
PMCID: PMC3609964  PMID: 23385609
9.  High flexion knee arthroplasty: the relationship between rotational angles and flexion angle after total knee arthroplasty 
The current patients required high flexion total knee arthroplasty (TKA). We hypothesized the patients who would get the high rotational angle just after TKA could gain high flexion knee 1 year after TKA. Sixty-three patients (average age: 70.6 years) were examined. In order to examine between the intraoperative rotational angles and the gained flexion angles after TKA, the patients were divided into two groups: the H group (more than 120°) and the L groups (less than 120°) by the gained flexion angles. The relationship between the flexion angles at 1 year after surgery and the intraoperative rotational angle had no significant correlation. But the rotational angles in the L group tended to be higher than the ones in the H group, and at only 30°, the L group gained significantly more rotational angle than the H group. These results might show that a tighter rotational stability induces a gain of higher flexion knee after TKA.
doi:10.1007/s12178-014-9215-1
PMCID: PMC4012152  PMID: 24658882
Total knee arthroplasty; Rotational angle; Flexion angle; PS type
10.  High flexion knee arthroplasty: the relationship between rotational angles and flexion angle after total knee arthroplasty 
The current patients required high flexion total knee arthroplasty (TKA). We hypothesized the patients who would get the high rotational angle just after TKA could gain high flexion knee 1 year after TKA. Sixty-three patients (average age: 70.6 years) were examined. In order to examine between the intraoperative rotational angles and the gained flexion angles after TKA, the patients were divided into two groups: the H group (more than 120°) and the L groups (less than 120°) by the gained flexion angles. The relationship between the flexion angles at 1 year after surgery and the intraoperative rotational angle had no significant correlation. But the rotational angles in the L group tended to be higher than the ones in the H group, and at only 30°, the L group gained significantly more rotational angle than the H group. These results might show that a tighter rotational stability induces a gain of higher flexion knee after TKA.
doi:10.1007/s12178-014-9215-1
PMCID: PMC4012152  PMID: 24658882
Total knee arthroplasty; Rotational angle; Flexion angle; PS type
11.  Extraosseous Extension Caused by Epidural Hematoma in Gaucher Disease Mimicking Malignant Bone Tumor 
JIMD Reports  2013;14:67-70.
Gaucher disease is an inherited autosomal-recessive disorder caused by the defective hydrolysis of glucocerebroside. The resultant hepatosplenomegaly, hematological changes, and orthopedic complications are the predominant symptoms. However, extraosseous manifestation of Gaucher disease, mimicking malignant bone tumor, is supposed to be rare. No reports of extraosseous manifestation of Gaucher disease caused by epidural hematoma were identified in the English literature. A 64-year-old man visited a nearby clinic for low back pain and was referred to our tumor clinic on suspicion of malignant bone tumor on sacral MRI. MRI revealed a demarcated solid lesion extending into the surrounding soft tissues on both sides of the sacral roots. During preoperative examination, he suffered from pathologic fracture in right mid-femur. We performed internal fixation with intramedullary nailing, simultaneously harvesting tissue specimens. Histopathological analysis showed aggregates of Gaucher cells in the right femur and hematoma in the sacrum. Epidural hematoma in Gaucher disease, usually attributed to thrombocytopenia, is a rare manifestation of skeletal complication, mimicking malignant processes.
doi:10.1007/8904_2013_285
PMCID: PMC4213331  PMID: 24363036
12.  Patient Selection Criteria for Periacetabular Osteotomy or Rotational Acetabular Osteotomy 
Background
Hip dysplasia is the most common cause of secondary osteoarthritis (OA). Periacetabular osteotomy (PAO) or rotational acetabular osteotomy (RAO) has been used as a joint-preserving procedure. However, the patient selection criteria are not clearly defined.
Questions/purposes
Based on a systematic review, we identified reported patient selection criteria for PAO or RAO.
Methods
We performed a systematic review of RAO and 18 studies met our inclusion criteria. For the PAO, the systemic review performed by Clohisy et al. was used.
Where Are We Now?
For patients with symptomatic hip dysplasia, lateral center-edge angle less than 10° to 30°, radiographic pre- or early OA, mean age at the time of surgery of 18 to 45 years, and improvement in joint congruency on AP radiograph with hip abduction, radiographic deformity correction consistently improved hip function in all studies. Radiographic OA progression was noted in 5% to 33% at 3.2 to 20 years postoperatively. Clinical score and prevention of radiographic OA progression of patients 50 years or older or with advanced stage were worse in younger patients or those with early stage.
Where Do We Need to Go?
The key challenges are (1) preoperative evaluation of articular cartilage; (2) indication for older patients; (3) prevention of secondary femoroacetabular impingement; and (4) intraarticular treatment combined with PAO or RAO.
How Do We Get There?
Future prospective, longitudinal cohort studies need to determine optimal patient selection criteria, risk factors for clinical failure, optimal deformity correction parameters, and the role of adjunctive surgical procedures.
doi:10.1007/s11999-012-2516-z
PMCID: PMC3492602  PMID: 22895690
13.  Heme oxygenase-1 modulates degeneration of the intervertebral disc after puncture in Bach 1 deficient mice 
European Spine Journal  2012;21(9):1748-1757.
Purpose
Intervertebral disc degeneration is considered to be a major feature of low back pain. Furthermore, oxidative stress has been shown to be an important factor in degenerative diseases such as osteoarthritis and is considered a cause of intervertebral disc degeneration. The purpose of this study was to clarify the correlation between oxidative stress and intervertebral disc degeneration using Broad complex-Tramtrack-Bric-a-brac and cap‘n’collar homology 1 deficient (Bach 1−/−) mice which highly express heme oxygenase-1 (HO-1). HO-1 protects cells from oxidative stress.
Methods
Caudal discs of 12-week-old and 1-year-old mice were evaluated as age-related models. Each group and period, 5 mice (a total of 20 mice, a total of 20 discs) were evaluated as age-related model. C9–C10 caudal discs in 12-week-old Bach 1−/− and wild-type mice were punctured using a 29-gauge needle as annulus puncture model. Each group and period, 5 mice (a total of 60 mice, a total of 60 discs) were evaluated. The progress of disc degeneration was evaluated at pre-puncture, 1, 2, 4, 8 and 12 weeks post-puncture. Radiographic, histologic and immunohistologic analysis were performed to compare between Bach 1−/− and wild-type mice.
Results
In the age-related model, there were no significant differences between Bach 1−/− and wild-type mice radiologically and histologically. However, in the annulus puncture model, histological scoring revealed significant difference at 8 and 12 weeks post-puncture. The number of HO-1 positive cells was significantly greater in Bach 1−/− mice at every period. The apoptosis rate was significantly lower at 1 and 2 weeks post-puncture in Bach 1−/− mice.
Conclusions
Oxidative stress prevention may avoid the degenerative process of the intervertebral disc after puncture, reducing the number of apoptosis cells. High HO-1 expression may also inhibit oxidative stress and delay the process of intervertebral disc degeneration.
doi:10.1007/s00586-012-2442-5
PMCID: PMC3459108  PMID: 22832873
Intervertebral disc; Oxidative stress; Heme oxygenase-1; Intervertebral disc degeneration
14.  Autologous Bone-Marrow Mesenchymal Stem Cell Implantation and Endothelial Function in a Rabbit Ischemic Limb Model 
PLoS ONE  2013;8(7):e67739.
Background
The purpose of this study was to determine whether autologous mesenchymal stem cells (MSCs) implantation improves endothelial dysfunction in a rabbit ischemic limb model.
Methods
We evaluated the effect of MSC implantation on limb blood flow (LBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, in rabbits with limb ischemia in which cultured MSCs were implanted (n = 20) or saline was injected as a control group (n = 20). LBF was measured using an electromagnetic flowmeter. A total of 106 MSCs were implanted into each ischemic limb.
Results
Histological sections of ischemic muscle showed that capillary index (capillary/muscle fiber) was greater in the MSC implantation group than in the control group. Laser Doppler blood perfusion index was significantly increased in the MSC implantation group compared with that in the control group. LBF response to ACh was greater in the MSC group than in the control group. After administration of NG-nitro-L-arginine, a nitric oxide synthase inhibitor, LBF response to ACh was similar in the MSC implantation group and control group. Vasodilatory effects of SNP in the two groups were similar.
Conclusions
These findings suggest that MSC implantation induces angiogenesis and augments endothelium-dependent vasodilation in a rabbit ischemic model through an increase in nitric oxide production.
doi:10.1371/journal.pone.0067739
PMCID: PMC3701528  PMID: 23861797
15.  Treatment of cartilage defects by subchondral drilling combined with covering with atelocollagen membrane induces osteogenesis in a rat model 
Journal of Orthopaedic Science  2013;18(4):627-635.
Background
The coverage of the atelocollagen membrane at the chondral defect after subchondral drilling might improve the beneficial effects for cartilage repair because of the prevention of scattering and accumulation of cells and growth factors from bone marrow within the chondral defect. On the other hand, it might block cells and factors derived from the synovium or cause high pressure in the chondral defect, resulting in prevention of cells and growth factors gushing out from the bone marrow, which leads to disadvantages for cartilage repair.
Method
We tested this hypothesis in a 2-mm-diameter chondral defect created in the articular cartilage of the patellar groove in a rat models. Defects were left untreated, or were drilled or drilled and covered with an atelocollagen membrane; healing was evaluated by histology and gene expression analysis using real-time polymerase chain reaction and immunohistochemistry.
Results
Membrane coverage induced bone tissue ingrowth into the punched chondral defect. At 1 week, expression of TGFβ, Sox9, Runx2, osteocalcin, Col1a1, and Col2a1 in the drilling group was significantly higher than in the covering group. At 4 weeks, expressions of TGFβ, Runx2, and Col1a1 were all significantly higher in the drilling group, while Sox9, osteocalcin, and Col2a1 were significantly higher in the covering group. Immunohistochemistry demonstrated Sox9, osteocalcin, and type II collagen on the bony reparative tissue in the covering group.
Conclusions
These results suggest that the atelocollagen membrane coverage resulted in inhibition of cartilage repair.
doi:10.1007/s00776-013-0379-0
PMCID: PMC3726928  PMID: 23564076
16.  The 86th Annual Meeting of the Japanese Orthopaedic Association 
Journal of Orthopaedic Science  2013;18(2):193-196.
doi:10.1007/s00776-013-0375-4
PMCID: PMC3608868  PMID: 23479205
18.  Mid-term results of acetabular reconstruction using a Kerboull-type acetabular reinforcement device 
International Orthopaedics  2011;36(1):23-26.
Purpose
The purpose of this study was to investigate the mid-term results of 32 acetabular reconstructions performed using a Kerboull-type acetabular reinforcement device and bone graft between June 1997 and January 2009.
Methods
The mean age of the patients at the time of surgery was 71.4 years (range 55–85). Patients were followed-up for a mean of 7.5 years (range 2.1–13.7). The acetabular bone defects according to the American Academy of Orthopaedic Surgeons system was type III for 29 hips and type IV for three hips. Bulk allografts were performed in 30 hips and morselised autografts (iliac bone) were performed in two hips. Clinical evaluations were made according to the criteria of Postel/Merle d’Aubigné.
Results
The mean pre-operative Postel/Merle d’Aubigné hip score was 7.0±2.9, and the final follow-up hip score was 12.6±2.8. Six hips showed radiographic loosening, and two hips required further revision. A Kaplan-Meier analysis showed that the five-year and ten-year survival rates were 96.9% and 92.3%, respectively, using further revision of the acetabular device as an end point.
Conclusion
Acetabular reconstruction using a Kerboull-type acetabular reinforcement device and bone graft gives satisfactory mid-term results.
doi:10.1007/s00264-011-1248-0
PMCID: PMC3251663  PMID: 21574052
19.  Diversity of angiogenesis among malignant bone tumors 
Molecular and Clinical Oncology  2012;1(1):131-136.
Several studies have demonstrated that angiogenesis assessed by microvessel density (MVD) correlates with patient prognosis in various types of cancer, whereas data regarding the relevance of angiogenesis and prognosis in malignant bone tumors are scarce and controversial. The aim of this study was to examine MVD in representative malignant bone tumors, such as osteosarcoma, chondrosarcoma and Ewing’s sarcoma, in order to clarify the role of angiogenesis in prognosis. A total of 69 patients with malignant bone tumors, including 44 osteosarcomas, 20 chondrosarcomas and 5 Ewing’s sarcomas, were reviewed retrospectively and treated at our hospital between 1980 and 2007. Biopsy or pre-chemotherapy surgical specimens were immunohistochemically stained with anti-CD34 antibody. The MVD values of osteosarcomas and Ewing’s sarcomas were significantly higher compared to chondrosarcoma. In osteosarcomas with high MVD, American Joint Committee on Cancer stage IIA, good histological response to chemotherapy was significantly correlated with better disease-free survival, while MVD was closely associated with age and chemotherapy response. In chondrosarcomas, the surgical margin (marginal and intralesional), MVD (high), tumor size (≥8) and histological grade (grades 2 and 3) significantly correlated with a shorter disease-free survival, while MVD was closely associated with age and histological grade. These findings showed that osteosarcomas and Ewing’s sarcomas were hypervascular, compared to chondrosarcomas. In osteosarcomas, hypervascularity induced good chemotherapy response, leading to better prognosis, while in chondrosarcomas, high MVD was associated with histological grade and predicted poor prognosis.
doi:10.3892/mco.2012.11
PMCID: PMC3956242  PMID: 24649135
angiogenesis; osteosarcoma; chondrosarcoma; Ewing’s sarcoma; prognosis
20.  Correlation between p38 mitogen-activated protein kinase and human telomerase reverse transcriptase in sarcomas 
Background
One of the major components of telomerase is the human telomerase reverse transcriptase (hTERT) as the catalytic protein. hTERT mRNA expression are reported to be associated with prognosis and tumor progression in several sarcomas. However, there is no clear understanding of the mechanisms of hTERT in human sarcomas. Recent studies have suggested that signals transmitted through p38 mitogen-activated protein kinase (MAPK) can increase or decrease hTERT transcription in human cells. The purpose of this study was to analyse the correlation between p38 MAPK and hTERT in sarcoma samples.
Methods
We investigated 36 soft tissue malignant fibrous histiocytomas (MFH), 24 liposarcomas (LS) and 9 bone MFH samples for hTERT and p38 MAPK expression. Quantitative detection of hTERT and p38 MAPK was performed by RT-PCR.
Results
There was a significant positive correlation between the values of hTERT and p38 MAPK in all samples (r = 0.445, p = 0.0001), soft tissue MFH (r = 0.352, p = 0.0352), LS (r = 0.704, p = 0.0001) and bone MFH samples (r = 0.802, p = 0.0093). Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis than other patients (p = 0.0036).
Conclusions
p38 MAPK may play a role in up-regulation of hTERT, and therefore, p38 MAPK may be a useful marker in the assessment of hTERT and patients' prognosis in sarcomas.
doi:10.1186/1756-9966-31-5
PMCID: PMC3296589  PMID: 22243975
p38 mitogen-activated protein kinase; human telomerase reverse transcriptase; malignant fibrous histiocytoma; liposarcoma
21.  Double bundle arthroscopic Anterior Cruciate Ligament reconstruction with remnant preserving technique using a hamstring autograft 
Background
Preservation of the Anterior Cruciate Ligament (ACL) remnant is important from the biological point of view as it enhances revascularization, and preserves the proprioceptive function of the graft construct. Additionally, it may have a useful biomechanical function. Double bundle ACL reconstruction has been shown to better replicate the native ACL anatomy and results in better restoration of the rotational stability than single bundle reconstruction.
Methods
We used the far anteromedial (FAM) portal for creation of the femoral tunnels, with a special technique for its preoperative localization using three dimensional (3D) CT. The central anteromedial (AM) portal was used to make a longitudinal slit in the ACL remnant to allow visualization of the tips of the guide pins during anatomical creation of the tibial tunnels within the native ACL tibial foot print. The use of curved hemostat allow retrieval of the wire loop from the apertures of the femoral tunnels through the longitudinal slit in the ACL remnant thereby, guarding against impingement of the reconstruction graft against the ACL remnant as well as the roof of the intercondylar notch.
Conclusion
Our technique allows for anatomical double bundle reconstruction of the ACL while maximally preserving the ACL remnant without the use of intra-operative image intensifier.
doi:10.1186/1758-2555-3-30
PMCID: PMC3284875  PMID: 22141394
22.  Shed Blood-derived Cells from Total Hip Arthroplasty Have Osteoinductive Potential: A Pilot Study 
Background
Cell therapy using autologous cells has been used in the treatment of various medical conditions. The mononuclear cell (MNC) fraction of bone marrow (BM) contains stem/progenitor cells that could contribute to osteogenesis and angiogenesis.
Questions/purposes
We asked whether MNCs derived from intraoperative shed blood (SB), consisting of peripheral blood and BM, have osteoinductive and angiogenic potential.
Methods
We harvested SB and BM from six patients undergoing THA. Isolated MNCs from SB and BM were analyzed by flow cytometry to evaluate the CD34+ cell fraction and 1 × 106 cells were seeded on an interconnective porous calcium hydroxyapatite ceramic (IP-CHA) and transplanted in the backs of athymic rats. IP-CHAs without cells were transplanted as controls and all composites were harvested after 4 and 8 weeks. Osteoinductive potential was evaluated by histologic observation, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) using anti-osteocalcin (OC) antibodies qualitatively and quantitatively. To evaluate angiogenic potential, capillary density was measured by immunohistochemistry using Isolectin B4 4 weeks after implantation.
Results
We found that CD34+ cells existed in SB-MNCs and there was a trend toward lower frequency compared with BM-MNCs. Histologic osteoinduction, OC expression, and capillary density were increased by transplantation of MNCs from SB. Similar results were achieved with MNCs from BM.
Conclusions
MNCs from SB have equivalent osteoinductive and angiogenic potential compared with those from BM.
Clinical Relevance
SB could be an attractive source for isolation of MNCs, enhancing osteoinduction and neovascularization, to augment the reconstruction of skeletal defects.
doi:10.1007/s11999-010-1444-z
PMCID: PMC3049633  PMID: 20585911
23.  Quantitative assessment of myelopathy patients using motor evoked potentials produced by transcranial magnetic stimulation 
European Spine Journal  2009;19(5):685-690.
Motor evoked potentials (MEPs) study using transcranial magnetic stimulation (TMS) may give a functional assessment of corticospinal conduction. But there are no large studies on MEPs using TMS in myelopathy patients. The purpose of this study is to confirm the usefulness of MEPs for the assessment of the myelopathy and to investigate the use of MEPs using TMS as a screening tool for myelopathy. We measured the MEPs of 831 patients with symptoms and signs suggestive of myelopathy using TMS. The MEPs from the abductor digiti minimi (ADM) and abductor hallucis (AH) muscles were evoked by transcranial magnetic brain stimulation. Central motor conduction time (CMCT) is calculated by subtracting the peripheral conduction time from the MEP latency. Later, 349 patients had surgery for myelopathy (operative group) and 482 patients were treated conservatively (nonoperative group). CMCTs in the operative group and nonoperative group were assessed. MEPs were prolonged in 711 patients (86%) and CMCTs were prolonged in 493 patients (59%) compared with the control patients. CMCTs from the ADM and AH in the operative group were significantly more prolonged than that in the nonoperative group. All patients in the operative group showed prolongation of MEPs or CMCTs or multiphase of the MEP wave. MEP abnormalities are useful for an electrophysiological evaluation of myelopathy patients. Moreover, MEPs may be effective parameters in spinal pathology for deciding the operative treatment.
doi:10.1007/s00586-009-1246-8
PMCID: PMC2899952  PMID: 20033461
Motor evoked potential; Transcranial magnetic stimulation; Central motor conduction time; Myelopathy; Diagnosis
24.  Stem/progenitor cells in closed suction drainage fluid after hip arthroplasty 
Acta Orthopaedica  2011;82(2):217-222.
Background and purpose
Drainage after surgery is commonly used, and the contents are generally discarded as clinical waste. We analyzed closed suction drainage fluid from hip arthroplasty patients to determine whether any multipotent stem cells were present that could be used as a source of cells for tissue regeneration.
Methods
Drainage fluid was obtained from 14 patients after hip arthroplasty on the day of surgery, the next day, and 2 days after surgery. Peripheral blood and bone marrow from the iliac crest were also obtained from the same patients during surgery. These samples were examined using regular flow cytometric profiling, and we performed quantitative immunoassays of stromal-derived factor-1 (SDF1) levels in the plasma. Mononuclear cells (MNCs) from these samples were also isolated and cultured. Fibroblastic adherent cells from MNC fractions were cultured in an osteogenic and a chondrogenic differentiation medium and were then evaluated for multipotentency.
Results and interpretation
Fibroblastic adherent cells were isolated from the mononuclear cell fraction of bone marrow and drainage fluid on the day of surgery, but they were not present in either the mononuclear cell fraction of the peripheral blood or the drainage fluid on the next day and 2 days after surgery. The cells from the drainage fluid on the day of surgery could differentiate in vitro into osteogenic and chondrogenic cells. SDF1 was elevated on the day of surgery, while CXCR4 was elevated on that day and the next day. This suggests that locally-induced SDF1 contributes to the mobilization of circulating CXCR4-positive cells. These results show that the drainage fluid collected on the day of surgery contains stem/progenitor cells that could be used for autologous cell-based therapy.
doi:10.3109/17453674.2011.566153
PMCID: PMC3235294  PMID: 21434846
25.  MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients 
Background
Interleukin (IL)-17 is an important factor in rheumatoid arthritis (RA) pathogenesis. MicroRNA (miRNA)s are a family of non coding RNAs and associated with human diseases including RA. The purpose of this study is to identify the miRNAs in the differentiation of IL-17 producing cells, and analyze their expression pattern in the peripheral blood mononuclear cells (PBMC) and synovium from RA patients.
Methods
IL-17 producing cells were expanded from CD4+T cell. MiRNA microarray was performed to identify the miRNAs in the differentiation of IL-17 producing cells. Quantitative polymerase chain reaction was performed to examine the expression patterns of the identified miRNAs in the PBMC and synovium from RA and osteoarthritis (OA) patients. Double staining combining in situ hybridization and immunohistochemistry of IL-17 was performed to analyze the expression pattern of identified miRNA in the synovium.
Results
Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells. The expression of miR-146a and IL-17 was higher than in PBMC in the patients with low score of Larsen grade and short disease duration. MiR-146a intensely expressed in RA synovium in comparison to OA. MiR-146a expressed intensely in the synovium with hyperplasia and high expression of IL-17 from the patients with high disease activity. Double staining revealed that miR-146a expressed in IL-17 expressing cells.
Conclusion
These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients. There is the possibility that miR-146a participates in the IL-17 expression.
doi:10.1186/1471-2474-11-209
PMCID: PMC2950393  PMID: 20840794

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