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1.  Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma 
Scientific Reports  2017;7:40187.
Ameloblastin (AMBN), the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Previously, we found that AMBN promoted osteogenic differentiation via the interaction between CD63 and integrin β1, leading to the inactivation of Src; however, how AMBN affects the malignant behavior of osteosarcoma is still unclear. Osteosarcoma affects the bone and is associated with poor prognosis because of the high rate of pulmonary metastases and drug resistance. Here we demonstrated that stable overexpression of AMBN induced apoptosis and suppressed colony formation and cell migration via the inactivation of Src-Stat3 pathway in human osteosarcoma cells. Moreover, AMBN induced chemosensitivity to doxorubicin. Thus, AMBN induced a tumor suppressive phenotype and chemosensitivity to doxorubicin via the AMBN-Src-Stat3 axis in osteosarcoma. Indeed, immunohistochemical expression of AMBN was significantly correlated with better outcome of osteosarcoma patients. Our findings suggest that AMBN can be a new prognostic marker and therapeutic target for osteosarcoma combined with conventional doxorubicin treatment.
doi:10.1038/srep40187
PMCID: PMC5214574  PMID: 28054649
2.  Differences in joint morphology between the knee and ankle affect the repair of osteochondral defects in a rabbit model 
Background
Although differences in the results of the bone marrow stimulation technique between the knee and ankle have been reported, a detailed mechanism for those differences has not been clarified. The purpose of this study was to examine whether morphological differences between the knee and ankle joint affect the results of drilling as treatment for osteochondral defects in a rabbit model.
Methods
Osteochondral defects were created at the knee and ankle joint in the rabbit. In the knee, osteochondral defects were created at the medial femoral condyle (MFC) and patellar groove (PG). At the ankle, defects were created in the talus at either a covered or uncovered area by the tibial plafond. After creating the osteochondral defect, drilling was performed. At 4, 8, and 12 weeks after surgery, repair of the osteochondral defects were evaluated histologically. The proliferation of rabbit chondrocytes and proteoglycan release of cartilage tissue in response to IL-1β were analyzed in vitro in both joints.
Results
At 8 weeks after surgery, hyaline cartilage repair was observed in defects at the covered area of the talus and the MFC. At 12 weeks, hyaline cartilage with a normal thickness was observed for the defect at the covered area of the talus, but not for the defect at the MFC. At 12 weeks, subchondral bone formation progressed and a normal contour of subchondral bone was observed on CT in the defect at the covered area of the talus. No significant differences in chondrocyte proliferation rate and proteoglycan release were detected between the knee and ankle in vitro.
Conclusions
Our results demonstrate that the covered areas of the talus show early and sufficient osteochondral repair compared to that of the knee and the uncovered areas of the talus. These results suggest that the congruent joint shows better subchondral repair prior to cartilage repair compared to that of the incongruent joint.
doi:10.1186/s13018-016-0444-4
PMCID: PMC5050570  PMID: 27716360
Ankle; Knee; Congruency; Subchondral bone; Rabbit
3.  Autologous bone grafts with MSCs or FGF-2 accelerate bone union in large bone defects 
Bacground
Although the contribution of fibroblast growth factor (FGF)-2 and mesenchymal stromal cells (MSCs) to bone formation is well known, few studies have investigated the combination of an autologous bone graft with FGF-2 or MSCs for large bone defects.
Methods
We studied an atrophic non-union model with a large bone defect, created by resecting a 10-mm section from the center of each femoral shaft of 12-week-old Sprague-Dawley rats. The periosteum of the proximal and distal ends of the femur was cauterized circumferentially, and excised portions were used in the contralateral femur as autologous bone grafts. The rats were randomized to three groups and given no further treatment (group A), administered FGF-2 at 20 μg/20 μL (group B), or 1.0 × 106 MSCs (group C). Radiographs were taken every 2 weeks up to 12 weeks, with CT performed at 12 weeks. Harvested femurs were stained with toluidine blue and evaluated using radiographic and histology scores.
Results
Radiographic and histological evaluation showed that bone union had been achieved at 12 weeks in group C, while group B showed callus formation and bridging callus but non-union, and in group A, callus formation alone was evident. Both radiographic and histological scores were significantly higher at 2, 4, 6, 8, 10, and 12 weeks in groups B and C than group A and also significantly higher in group C than group B at 12 weeks.
Conclusions
These data suggest that autologous bone grafts in combination with MSCs benefit difficult cases which cannot be treated with autologous bone grafts alone.
doi:10.1186/s13018-016-0442-6
PMCID: PMC5037630  PMID: 27669690
Large bone defects; Autologous bone grafts; Atrophic non-union model; Mesenchymal stromal cells (MSCs); Fibroblast growth factor-2 (FGF-2)
4.  MicroRNAs and Bone Regeneration 
Current Genomics  2015;16(6):441-452.
Bone has multiple functions, both morphologically and physiologically, and it frequently features in the pathological condition, including fracture and osteoporosis. For bone regeneration therapy, the regulation of osteoblast differentiation is important. MicroRNA (miRNA)s are short noncoding RNA which regulate gene expression at the post-transcriptional level. MiRNAs play an important role not only in a variety of other cellular processes including differentiation, proliferation, and apoptosis but also in the pathogenesis of human diseases. Recently, miRNAs have been known to participate in osteoblast differentiation by regulating several signaling pathways including transcription factors. New insight into the mechanism during osteogenes is affected by miRNAs has been gained. Moreover, therapeutic trials for bone diseases including osteoporosis, fracture and bone defects targeting miRNAs have been examined in animal models. MiRNA therapy will enable development of a bone regeneration therapy.
doi:10.2174/1389202916666150817213630
PMCID: PMC4765532  PMID: 27019619
Bone; Osteoblast; microRNA; Transcription factor; Signaling pathway.
5.  Unique Anatomic Feature of the Posterior Cruciate Ligament in Knees Associated With Osteochondritis Dissecans 
Orthopaedic Journal of Sports Medicine  2016;4(5):2325967116648138.
Background:
Osteochondritis dissecans (OCD) of the knee is a disorder in juveniles and young adults; however, its etiology still remains unclear. For OCD at the medial femoral condyle (MFC), it is sometimes observed that the lesion has a connection with fibers of the posterior cruciate ligament (PCL). Although this could be important information related to the etiology of MFC OCD, there is no report examining an association between the MFC OCD and the PCL anatomy.
Purpose:
To investigate the anatomic features of knees associated with MFC OCD, focusing especially on the femoral attachment of the PCL, and to compare them with knees associated with lateral femoral condyle (LFC) OCD and non-OCD lesions.
Study Design:
Case-control study; Level of evidence, 3.
Methods:
We retrospectively reviewed 39 patients (46 knees) with OCD lesions who had undergone surgical treatment. Using magnetic resonance imaging (MRI) scans, the PCL attachment at the lateral wall of the MFC was measured on the coronal sections, and the knee flexion angle was also measured on the sagittal sections. As with non-OCD knees, we reviewed and analyzed 25 knees with anterior cruciate ligament (ACL) injuries and 16 knees with meniscal injuries.
Results:
MRIs revealed that the femoral PCL footprint was located in a significantly more distal position in the patients with MFC OCD compared with patients with LFC OCD and ACL and meniscal injuries. There was no significant difference in knee flexion angle among the 4 groups.
Conclusion:
The PCL in patients with MFC OCD attached more distally at the lateral aspect of the MFC compared with knees with LFC OCD and ACL and meniscal injuries.
doi:10.1177/2325967116648138
PMCID: PMC4887879  PMID: 27294170
osteochondritis dissecans; posterior cruciate ligament; femoral footprint; anatomic feature
6.  Repair Mechanism of Osteochondral Defect Promoted by Bioengineered Chondrocyte Sheet 
Tissue Engineering. Part A  2014;21(5-6):1131-1141.
Cell sheet engineering has developed as a remarkable method for cell transplantation. In the field of cartilage regeneration, several studies previously reported that cartilage defects could be regenerated by transplantation of a chondrocyte sheet using cell sheet engineering. However, it remains unclear how such a thin cell sheet could repair a deep cartilage defect. We, therefore, focused on the mechanism of cartilage repair using cell sheet engineering in this study. Chondrocyte sheets and synovial cell sheets were fabricated using cell sheet engineering, and these allogenic cell sheets were transplanted to cover an osteochondral defect in a rat model. Macroscopic and histological evaluation was performed at 4 and 12 weeks after transplantation. Analysis of the gene expression of each cell sheet and of the regenerated tissue at 1 week after transplantation was performed. In addition, green fluorescent protein (GFP) transgenic rats were used as donors (transplanted chondrocyte sheets) or recipients (osteochondral defect models) to identify the cell origin of regenerated cartilage.
Cartilage repair was significantly better in the group implanted with a chondrocyte sheet than in that with a synovial cell sheet. The results of gene expression analysis suggest that the possible factor contributing to cartilage repair might be TGFβ1. Cell tracking experiments using GFP transgenic rats showed that the regenerated cartilage was largely composed of cells derived from the transplanted chondrocyte sheets.
doi:10.1089/ten.tea.2014.0310
PMCID: PMC4356224  PMID: 25396711
8.  Does Expression of Glucose Transporter Protein-1 Relate to Prognosis and Angiogenesis in Osteosarcoma? 
Background
The survival of patients who present with nonmetastatic extremity osteosarcoma has dramatically improved, but there are some patients who do not respond to chemotherapy. The ability to identify patients with a poorer prognosis might allow us to target different therapy for these patients. Glucose transporter protein-1 (Glut-1), one of the key factors in glucose metabolism, has been reported to be an independent prognostic factor in various tumors. However, little is known about the role of the Glut-1 pathway in osteosarcoma.
Questions/purposes
We asked (1) if Glut-1 expression is a prognostic marker for survival in patients with osteosarcoma, and (2) if there is a relationship between Glut-1 expression and tumor angiogenesis.
Patients and Methods
Thirty-seven patients with resectable high-grade osteosarcomas treated between 1982 and 2007 were reviewed retrospectively. Patients were excluded if representative biopsy material and followup data were not available. The expression of Glut-1 and the number of CD34-positive microvessels for angiogenic activity were measured immunohistochemically. The median followup was 6 years 6 months (range, 11–211 months). Survival analyses were evaluated using the Kaplan-Meier method and the Cox proportional hazards model. The association between Glut-1 expression and microvessel density was analyzed using Student’s t-test and chi-square test. For 12 (32.4%) of 37 patients with osteosarcoma, the expression of Glut-1 was positive, with four patients (10.8%) showing strong expression of Glut-1 protein.
Results
The expression of Glut-1 correlated with a shorter disease-free survival period (relative risk, 20.13; 95% CI, 1.77–229.3; p = 0.0016). The microvessel density mean value of positive Glut-1 expression (mean ± SD, 26.5 ± 19.4) was lower than that of negative expression (mean ± SD, 46.4 ± 35.3; Student’s t-test, p = 0.038). When more than 50 was defined as a high microvessel density, positive expression of Glut-1 was significantly associated with low microvessel density (chi-square test, p = 0.049).
Conclusions
These findings indicate that Glut-1 is a potential predictor of survival in patients with osteosarcoma and that glucose metabolism may be negatively associated with angiogenesis. If substantiated in larger numbers of patients, these findings might stimulate the development of novel treatments for patients with a poorer prognosis.
Level of Evidence
Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-014-3910-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-014-3910-5
PMCID: PMC4390948  PMID: 25193692
9.  Bach1 deficiency reduces severity of osteoarthritis through upregulation of heme oxygenase-1 
Introduction
BTB and CNC homology 1 (Bach1) is a transcriptional repressor of Heme oxygenase-1 (HO-1), which is cytoprotective through its antioxidant effects. The objective of this study was to define the role of Bach1 in cartilage homeostasis and osteoarthritis (OA) development using in vitro models and Bach1-/- mice.
Methods
HO-1 expression in Bach1-/- mice was analyzed by real-time PCR, immunohistochemistry and immunoblotting. Knee joints from Bach1-/- and wild-type mice with age-related OA and surgically-induced OA were evaluated by OA scoring systems. Levels of autophagy proteins and superoxide dismutase 2 (SOD2) were determined by immunohistochemistry. The relationship between HO-1 and the protective effects for OA was determined in chondrocytes treated with small interfering RNA (siRNA) targeting HO-1 gene.
Results
HO-1 expression decreased with aging in articular cartilages and menisci of mouse knees. Bach1-/- mice showed reduced severity of age-related OA and surgically-induced OA compared with wild-type mice. Microtubule-associated protein 1 light chain 3 (LC3), autophagy marker, and SOD2 were increased in articular cartilage of Bach1-/- mice compared with wild-type mice. Interleukin-1β (IL-1β) induced a significant increase in Adamts-5 in wild-type chondrocytes but not in Bach1-/- chondrocytes. The expression of SOD2 and the suppression of apoptosis in Bach1-/- chondrocytes were mediated by HO-1.
Conclusions
Bach1 deficiency reduces the severity of OA-like changes. This may be due to maintenance of cartilage homeostasis and joint health by antioxidant effects through HO-1 and downregulation of extracellular matrix degrading enzymes. These results suggest that inactivation of Bach1 is a novel target and signaling pathway in OA prevention.
doi:10.1186/s13075-015-0792-1
PMCID: PMC4603301  PMID: 26458773
10.  Prognostic value of SS18–SSX fusion type in synovial sarcoma; systematic review and meta-analysis 
SpringerPlus  2015;4:375.
SS18–SSX (formerly called SYT–SSX) fusion gene has been established clinically as a molecular diagnostic test for synovial sarcoma, but the prognostic value of the fusion gene variant for survival is controversial. The objective of this systematic review is to provide an up-to-date and unprecedented summary of the prognostic impact of SS18–SSX fusion type in synovial sarcoma. Studies evaluating SS18–SSX fusion type as a prognostic marker in synovial sarcoma were systematically searched for in MEDLINE, EMBASE, and Web of Science. Comparative analysis of the pooled hazard ratios (HR) between fusion types was carried out, in order to assess the likelihood of overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and metastasis-free survival (MFS). A total of 10 studies comprising 902 patients with synovial sarcoma were considered for the meta-analysis. The pooled HR for eight eligible studies evaluating for OS or DSS was 1.28 (95% confidence interval: 0.81–2.00), suggesting no significant difference between SS18–SSX1 and SS18–SSX2 (P = 0.29). For seven studies which evaluated for PFS or MFS, the presence of SS18–SSX1 may indicate a lower survival probability than that of SS18–SSX2, although the effect did not reach a level of statistical significance (P = 0.09). There was no significant difference in OS or DSS between SS18–SSX1 and SS18–SSX2, but there were indications of SS18–SSX1 being an unfavorable prognostic factor of PFS or MFS. Further studies including cohorts with a longer follow-up period are needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s40064-015-1168-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s40064-015-1168-3
PMCID: PMC4514732  PMID: 26217552
Meta-analysis; Synovial sarcoma; Fusion gene; SS18–SSX; Survival
11.  Low femoral antetorsion as a risk factor for bony impingement after bipolar hemiarthroplasty 
Introduction
Reports of dislocation after bipolar hemiarthroplasty (BHA) abound in literature, and several studies have mentioned the factors that are associated with an increased risk of dislocation. However, there is no report detailing the pattern of impingement in BHA and how femoral antetorsion can affect the range of motion (ROM) after BHA.
Purpose
The purpose of this study was to evaluate the pattern of impingement in BHA and whether femoral antetorsion affects the ROM after BHA using three-dimensional (3D) dynamic motion analysis.
Methods
Using the computed tomography (CT) data of 60 patients (60 hips), including 31 men and 29 women who underwent BHA for the treatment of idiopathic osteonecrosis (ION) of the femoral head, we calculated the antetorsion of the femoral neck, ROM of flexion (Flex), internal rotation (Int-R), and external rotation (Ext-R) using a CT-based 3D simulation software. We evaluated the pattern of impingement and the relationship between femoral antetorsion and ROM in BHA. As for the implant position in the 3D simulation software, the anteversion of the femoral implant was set to be the same as the natural antetorsion of the femoral neck and neck length was set to be the standard neck in all cases.
Results
This study revealed the mechanism of impingement in BHA: (1) bone to bone impingement and (2) implant to bone impingement. We found a significant decrease in the ROM of Flex and Int-R inversely proportional to the femoral antetorsion. In patients with lower femoral antetorsion, the ROM of Flex and Int-R decreased due to bony impingement (the anterior great trochanteric region of the femur impinges on the anteroinferior edge of the anteroinferior iliac spine). Whereas, high anteversion of the femoral implant may decrease the ROM of Ext-R; however, our results also showed that even the lowest ROM of Ext-R with 10° hip extension was over 40°.
Conclusions
We demonstrated that lower femoral antetorsion substantially affects the ROM of Flex and Int-R due to bony impingement. For these patients, there should be consideration given to retaining femoral “anterior offset” in BHA.
doi:10.1186/s13018-015-0248-y
PMCID: PMC4501289  PMID: 26149008
Bipolar hemiarthroplasty; Three-dimensional motion analysis; Femoral antetorsion; Bony impingement; Dislocation; Impingement pattern
12.  Symmetrical peripheral gangrene caused by septic shock 
We report three cases of symmetrical peripheral gangrene (SPG) caused by septic shock. Most of sepsis survivors with SPG require amputation of the affected extremities. To preserve the length of the thumb and fingers, we performed surgical amputation and used flaps to cover the amputated peripheral extremities.
doi:10.3109/23320885.2015.1041529
PMCID: PMC4793794  PMID: 27252971
Flap; septic shock; surgical amputation; symmetrical peripheral gangrene
13.  Large animal models in experimental knee sports surgery: focus on clinical translation 
Large animal models play a crucial role in sports surgery of the knee, as they are critical for the exploration of new experimental strategies and the clinical translation of novel techniques. The purpose of this contribution is to provide critical aspects of relevant animal models in this field, with a focus on paediatric anterior cruciate ligament (ACL) reconstruction, high tibial osteotomy, and articular cartilage repair. Although there is no single large animal model strictly replicating the human knee joint, the sheep stifle joint shares strong similarities. Studies in large animal models of paediatric ACL reconstruction identified specific risk factors associated with the different surgical techniques. The sheep model of high tibial osteotomy is a powerful new tool to advance the understanding of the effect of axial alignment on the lower extremity on specific issues of the knee joint. Large animal models of both focal chondral and osteochondral defects and of osteoarthritis have brought new findings about the mechanisms of cartilage repair and treatment options. The clinical application of a magnetic device for targeted cell delivery serves as a suitable example of how data from such animal models are directly translated into in clinical cartilage repair. As novel insights from studies in these translational models will advance the basic science, close cooperation in this important field of clinical translation will improve current reconstructive surgical options and open novel avenues for regenerative therapies of musculoskeletal disorders.
doi:10.1186/s40634-015-0025-1
PMCID: PMC4545948  PMID: 26914877
Musculoskeletal disorders; Large animal models; Sheep; Paediatric anterior cruciate ligament reconstruction; High tibial osteotomy; Articular cartilage repair; Osteoarthritis; Clinical studies; Mesenchymal stem cells; Magnetic-assisted delivery
14.  Evaluation of Single-Bundle versus Double-Bundle PCL Reconstructions with More Than 10-Year Follow-Up 
The Scientific World Journal  2015;2015:751465.
Background. Posterior cruciate ligament (PCL) injuries are not rare in acute knee injuries, and several recent anatomical studies of the PCL and reconstructive surgical techniques have generated improved patient results. Now, we have evaluated PCL reconstructions performed by either the single-bundle or double-bundle technique in a patient group followed up retrospectively for more than 10 years. Methods. PCL reconstructions were conducted using the single-bundle (27 cases) or double-bundle (13 cases) method from 1999 to 2002. The mean age at surgery was 34 years in the single-bundle group and 32 years in the double-bundle group. The mean follow-up period was 12.5 years. Patients were evaluated by Lysholm scoring, the gravity sag view, and knee arthrometry. Results. The Lysholm score after surgery was 89.1 ± 5.6 points for the single-bundle group and 91.9 ± 4.5 points for the double-bundle group. There was no significant difference between the methods in the side-to-side differences by gravity sag view or knee arthrometer evaluation, although several cases in both groups showed a side-to-side difference exceeding 5 mm by the latter evaluation method. Conclusions. We found no significant difference between single- and double-bundle PCL reconstructions during more than 10 years of follow-up.
doi:10.1155/2015/751465
PMCID: PMC4333278  PMID: 25729771
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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