Shinichi Miyazawa

Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model

OBJECTIVE To investigate the effect of the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), on joint inflammation and cartilage degeneration in a collagen antibody-induced arthritis (CAIA) mouse model. METHODS CAIA mice were given daily subcutaneous injections of various concentrations of TSA (0, 0.5, 1.0, and 2.0 mg/kg) and various parameters were monitored for 14 days. On Day 15, the hind paws were examined histologically. To investigate the effects of TSA on the expressions of matrix metalloproteinase (MMP)-3, MMP-13, tissue inhibitor of MMP-1 (TIMP-1), and acetyl-H4 by chondrocytes, another group of mice was sacrificed on Day 6. In vitro direct effect of TSA was examined by real-time PCR for mRNA of type II collagen, aggrecan, MMP-3, and MMP-13 in murine chondrogenic ATDC5 cells after pro-inflammatory cytokine stimulation. RESULTS In the TSA-treated group, clinical arthritis was significantly ameliorated in a dose-dependent manner. The severity of synovial inflammation and the cartilage destruction score were significantly lower in the TSA 2.0 mg/kg group compared to the other TSA-treated groups. On immunohistochemistry, the number of MMP-3 and MMP-13-positive chondrocytes was significantly lower in the TSA 2.0 mg/kg group than in the control group. In contrast, the number of TIMP-1-positive cells and acetyl-histone H4-positive cells was significantly higher in the TSA 2.0mg/kg group than in the control group. TSA suppressed interleukin 1-beta and tumor necrosis factor-alpha-stimulated up-regulation of MMP-3, but not MMP-13 mRNA expression by ATDC5. CONCLUSION The systemic administration of TSA ameliorated synovial inflammation in CAIA mice. Subsequently cartilage destruction was also suppressed by TSA, at least in part, by modulating chondrocyte gene expression.

Intra-articular injection of interleukin-4 decreases nitric oxide production by chondrocytes and ameliorates subsequent destruction of cartilage in instability-induced osteoarthritis in rat knee joints

OBJECTIVE To investigate the in vitro and in vivo effects of interleukin (IL)-4 on mechanical stress-induced nitric oxide (NO) expression by chondrocytes, and destruction of cartilage and NO production in an instability-induced osteoarthritis (OA) model in rat knee joints, respectively. MATERIALS AND METHODS Cyclic tensile stress (CTS; 0.5Hz and 7% elongation) was applied to cultured normal rat chondrocytes with or without pre-incubation with recombinant rat IL-4 (rrIL-4). Inducible NO synthase (iNOS) mRNA expression and NO production were examined with real-time polymerase chain reaction and the Griess reaction, respectively. OA was induced in rat knee joints by transection of the anterior cruciate and medial collateral ligaments and resection of the medial meniscus. rrIL-4 (10, 50, and 100 ng/joint/day) was injected intra-articularly, and knee joint samples were collected 2, 4, and 6 weeks after surgery. Cartilage destruction was evaluated by the modified Mankin score and Osteoarthritis Research Society International scoring system on paraffin-embedded sections stained with safranin O. Cleavage of aggrecan and NO production were examined by immunohistochemistry for aggrecan neoepitope (NITEGE) and of nitrotyrosine (NT), respectively. RESULTS rrIL-4 down-regulated CTS-induced iNOS mRNA expression and NO production by chondrocytes. The intra-articular injection of rrIL-4 gave rise to a limited, but significant amelioration of cartilage destruction, prevention of loss of aggrecan, and decrease in the number of NT-positive chondrocytes, an effect that was not dose-dependent. CONCLUSION The present study suggests that IL-4 may exert chondroprotective properties against mechanical stress-induced cartilage destruction, at least in part, by inhibiting NO production by chondrocytes.

Postoperative change in medial meniscal length in concurrent all-inside meniscus repair with anterior cruciate ligament reconstruction

PurposeMeniscus repair can restore meniscal function that transfers the axial compressive force to circumferential tensile strain. However, few reports have investigated the relationship between concurrent meniscus repair with acute anterior cruciate ligament (ACL) reconstruction and postoperative meniscal position. This study aimed to evaluate medial meniscal size and clinical results in patients who underwent ACL reconstruction and concomitant all-inside medial meniscus repair.MethodsTwenty patients underwent ACL reconstruction and concurrent medial meniscus repair of a peripheral longitudinal tear using the FasT-Fix meniscal repair device. Medial tibial plateau length (MTPL) and width (MTPW) were determined by radiographic images. We evaluated the Lysholm score, anteroposterior instability, meniscal healing and magnetic resonance imaging (MRI)-based medial meniscal length (MML) and width (MMW). Correlations between MRI-based meniscal size, radiographic measurement and height were investigated.ResultsAll patients showed complete healing of the repaired meniscus in arthroscopic evaluation. However, one patient needed a subsequent meniscus repair during the follow-up period. Lysholm score and anteroposterior instability improved significantly. A better correlation was observed between MMW and MTPW than between MML and MTPL. Concurrent all-inside medial meniscus repair with ACL reconstruction significantly increased MML percentage (%MML) (100 MML/MTPL) but did not affect MMW percentage (%MMW) (100 MMW/MTPW).ConclusionsConcurrent all-inside medial meniscus repair with ACL reconstruction had satisfactory clinical results. %MML was increased by concurrent medial meniscus repair without affecting %MMW. Our results suggest that medial meniscus repair associated with ACL reconstruction may restore meniscal function by adjusting the anteroposterior length of the torn medial meniscus.

Postoperative change in the length and extrusion of the medial meniscus after anterior cruciate ligament reconstruction

PurposeThe medial meniscus is a secondary stabilizer of anterior tibial translation in anterior cruciate ligament (ACL)-deficient knees. ACL reconstruction effectively restores an increased anterior tibial translation in the ACL-deficient knee. However, knee osteoarthritis sometimes develops in ACL-reconstructed patients during a long-term follow-up period. We hypothesized that the medial meniscal position would be different between the ACL-deficient and reconstructed knees. The aim of this study was to investigate pre-operative and postoperative location of the medial meniscus in patients who underwent ACL reconstruction.MethodsACL-reconstructed knees (28 knees) and normal knees (27 knees) were investigated. Medial tibial plateau length (MTPL) and medial tibial plateau width (MTPW) were determined using radiographic images. Magnetic resonance imaging (MRI)-based medial meniscal length (MML), medial meniscal width (MMW), and medial meniscal extrusion (MME) were measured. Postoperative change in the MML, MMW, and MME were evaluated and compared with those in normal knees.ResultsNo significant differences between the ACL-deficient (pre-operative) and normal groups were noted. The ACL-reconstructed (postoperative) group showed an increase in the MML, in the percentage of the MML (%MML = 100 MML/MTPL), and in the MME. Significant differences between postoperative and normal groups were observed in the MML, %MML, and MME. MMW and MMW percentage (100 MMW/MTPW) were similar in all groups.ConclusionsThe anteroposterior length and radial extrusion of the medial meniscus increased after ACL reconstruction. Transposition of the medial meniscus may be a possible cause of developing further degenerative knee joint disorders after ACL reconstruction.

Pullout repair of a medial meniscus posterior root tear using a FasT-Fix ® all-inside suture technique

A medial meniscus posterior root tear (MMPRT) may increase the tibiofemoral contact pressure by decreasing the tibiofemoral contact area. Meniscal dysfunction induced by posterior root injury may lead to the development of osteoarthritic knees. Repair of a MMPRT can restore medial meniscus (MM) function and prevent knee osteoarthritis progression. Several surgical procedures have been reported for treating a MMPRT. However, these procedures are associated with several technical difficulties. Here, we describe a technique to stabilize a torn MM posterior root using the FasT-Fix® all-inside meniscal suture device and a new aiming device. The uncut free-end of the FasT-Fix® suture can be used as a thread for transtibial pullout repair. Our procedure might help overcome the technical difficulties in arthroscopic treatment of a MMPRT.

Comparison between normal and loose fragment chondrocytes in proliferation and redifferentiation potential

PurposeLoose fragments in osteochondritis dissecans (OCD) of the knee require internal fixation. On the other hand, loose fragments derived from spontaneous osteonecrosis of the knee (SONK) are usually removed. However, the difference in healing potential between OCD- and SONK-related loose fragments has not been elucidated. In this study, we investigated proliferative activity and redifferentiation potential of normal cartilage-derived and loose fragment-derived chondrocytes.MethodsCells were prepared from normal articular cartilages and loose fragment cartilages derived from knee OCD and SONK. Cellular proliferation was compared. Redifferentiation ability of pellet-cultured chondrocytes was assessed by real-time PCR analyses. Mesenchymal differentiation potential was investigated by histological analyses. Positive ratio of a stem cell marker CD166 was evaluated in each cartilaginous tissue.ResultsNormal and OCD chondrocytes showed a higher proliferative activity than SONK chondrocytes. Chondrogenic pellets derived from normal and OCD chondrocytes produced a larger amount of safranin O-stained proteoglycans compared with SONK-derived pellets. Expression of chondrogenic marker genes was inferior in SONK pellets. The CD166-positive ratio was higher in normal cartilages and OCD loose fragments than in SONK loose fragments.ConclusionsThe OCD chondrocytes maintained higher proliferative activity and redifferentiation potential compared with SONK chondrocytes. Our results suggest that chondrogenic properties of loose fragment-derived cells and the amount of CD166-positive cells may affect the repair process of osteochondral defects.

The anterior cruciate ligament-lateral meniscus complex: A histological study

ABSTRACT The anterior root of the lateral meniscus (LM) dives underneath the tibial attachment of the anterior cruciate ligament (ACL). Although the distinct role of meniscal attachments has been investigated, the relationship between the LM anterior insertion (LMAI) and ACL tibial insertion (ACLTI) remains unclear. This study histologically analyzed the LMAI and ACLTI. Samples were divided into four regions in an anterior-to-posterior direction. Histological measurements of these insertion sites were performed using safranin O-stained coronal sections. Distribution and signal densities of type I and II collagen were quantified. The ACLTI and LMAI formed the ACL–LM complex via fiber connections. The anterior part of the ACLTI had a widespread attachment composed of dense fibers. Attachment fibers of the LMAI became dense and wide gradually at the middle-to-posterior region. The ACL–LM transition zone (ALTZ) was observed between the LMAI and the lateral border of the ACLTI at the middle part of the ACL tibial footprint. Type II collagen density of the LMAI was higher than that of the ACLTI and ALTZ. Our results can help create an accurate tibial bone tunnel within the dense ACL attachment during ACL reconstruction surgery.

Location of the tibial tunnel aperture affects extrusion of the lateral meniscus following reconstruction of the anterior cruciate ligament

The anterior root of the lateral meniscus provides functional stability to the meniscus. In this study, we evaluated the relationship between the position of the tibial tunnel and extrusion of the lateral meniscus after anterior cruciate ligament reconstruction, where extrusion provides a proxy measure of injury to the anterior root. The relationship between extrusion and tibial tunnel location was retrospectively evaluated from computed tomography and magnetic resonance images of 26 reconstructed knees, contributed by 25 patients aged 17–31 years. A measurement grid was used to localize the position of the tibial tunnel based on anatomical landmarks identified from the three‐dimensional reconstruction of axial computed tomography images of the tibial plateaus. The reference point‐to‐tibial tunnel distance (mm) was defined as the distance from the midpoint of the lateral edge of the grid to the posterolateral aspect of the tunnel aperture. The optimal cutoff of this distance to minimize post‐operative extrusion was identified using receiver operating curve analysis. Extrusion of the lateral meniscus was positively correlated to the reference point‐to‐tibial tunnel distance (r 2 = 0.64; p < 0.001), with a cutoff distance of 5 mm having a sensitivity to extrusion of 83% and specificity of 93%. The mean extrusion for a distance >5 mm was 0.40 ± 0.43 mm, compared to 1.40 ± 0.51 mm for a distance ≤5 mm (p < 0.001). Therefore, a posterolateral location of the tibial tunnel aperture within the footprint of the anterior cruciate ligament decreases the reference point‐to‐tibial tunnel distance and increases extrusion of the lateral meniscus post‐reconstruction.

A new aiming guide can create the tibial tunnel at favorable position in transtibial pullout repair for the medial meniscus posterior root tear

INTRODUCTION Injuries to the medial meniscus (MM) posterior root lead to accelerated cartilage degeneration of the knee. An anatomic placement of the MM posterior root attachment is considered to be critical in transtibial pullout repair of the medial meniscus posterior root tear (MMPRT). However, tibial tunnel creation at the anatomic attachment of the MM posterior root is technically difficult using a conventional aiming device. The aim of this study was to compare two aiming guides. We hypothesized that a newly-developed guide, specifically designed, creates the tibial tunnel at an adequate position rather than a conventional device. MATERIALS AND METHODS Twenty-six patients underwent transtibial pullout repairs. Tibial tunnel creation was performed using the Multi-use guide (8 cases) or the PRT guide that had a narrow twisting/curving shape (18 cases). Three-dimensional computed tomography images of the tibial surface were evaluated using the Tsukadas measurement method postoperatively. Expected anatomic center of the MM posterior root attachment and tibial tunnel center were evaluated using the percentage-based posterolateral location on the tibial surface. Percentage distance between anatomic center and tunnel center was calculated. RESULTS Anatomic center of the MM posterior root footprint located at a position of 78.5% posterior and 39.4% lateral. Both tunnels were anteromedial but tibial tunnel center located at a more favorable position in the PRT group: percentage distance was significantly smaller in the PRT guide group (8.7%) than in the Multi-use guide group (13.1%). DISCUSSION The PRT guide may have great advantage to achieve a more anatomic location of the tibial tunnel in MMPRT pullout repair. LEVEL OF EVIDENCE III.

The figure-of-nine leg position for anatomic anterior cruciate ligament reconstruction.

Anatomic double-bundle anterior cruciate ligament (ACL) reconstruction can restore the function and kinematics of the knee in ACL-deficient patients. Several outside-in drilling systems for accurate femoral tunnel creations have been developed. However, the femoral tunnel creation at the lower position of the intercondylar notch can be difficult in a usual leg position with the knee flexed at 90° without varus stress. This technical note describes that the figure-of-nine leg position provides a better arthroscopic view to safely clean up the ACL femoral footprint located at the lower area of the lateral intercondylar wall. This position is useful to create the optimal femoral tunnels using the outside-in drilling technique, without damaging the lateral meniscus posterior root, lateral tibial eminence, and supplemental fibers that bridge the gap between the lateral meniscus and the ACL tibial insertion.