Shuji Taketomi

Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2

Significance Here we demonstrate that Hes1, an important target of Notch signaling, modulated pathogenesis of osteoarthritis by using Col2a1-CreERT;Hes1fl/fl mice. Adamts5 and Mmp13, catabolic enzymes that break down cartilage matrix, were induced by Hes1. Additionally, microarray analysis and ChIP-seq revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. CaMK2δ was activated during osteoarthritis development. CaMK2δ formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1fl/fl mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-CreERT;Hes1fl/fl mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.

Three-Dimensional Fluoroscopic Navigation Guidance for Femoral Tunnel Creation in Revision Anterior Cruciate Ligament Reconstruction

Revision anterior cruciate ligament (ACL) reconstruction is accompanied by several technical challenges that must be addressed, such as a primary malpositioned bone tunnel, pre-existing hardware, or bone defects due to tunnel expansion. We describe a surgical technique used to create an anatomic femoral socket using a 3-dimensional (3D) fluoroscopy-based navigation system in technically demanding revision cases. After a reference frame is rigidly attached to the femur, an intraoperative image of the distal femur is obtained, which is transferred to a navigation system and reconstructed into a 3D image. A navigation computer helps the surgeon to visualize the whole image of the lateral wall of the femoral notch, even if the natural morphology of the intercondylar notch has been destroyed by the primary procedure. In addition, the surgeon can also confirm the position of the previous bone tunnel aperture, the previous exit of the femoral tunnel, and the presence of any pre-existing hardware on the navigation monitor. When a new femoral guidewire for the revision procedure is placed, the virtual femoral tunnel is overlaid on the reconstructed 3D image in real time. At our institution, 12 patients underwent 1-stage revision ACL procedures with the assistance of this computer navigation system, and the grafts were securely fixed in anatomically created tunnels in all cases. This technology can assist surgeons in creating anatomic femoral tunnels in technically challenging revision ACL reconstructions.

Remnant-Preserving Anterior Cruciate Ligament Reconstruction Using a Three-Dimensional Fluoroscopic Navigation System

Introduction Recently, remnant-preserving anterior cruciate ligament (ACL) reconstruction has been increasingly performed to achieve revascularization, cell proliferation, and recovery of high-quality proprioception. However, poor arthroscopic visualization makes accurate socket placement during remnant-preserving ACL reconstruction difficult. This study describes a surgical technique used to create an anatomical femoral socket with a three-dimensional (3D) fluoroscopy based navigation system during technically demanding remnant-preserving ACL reconstruction. Surgical Technique After a reference frame was attached to the femur, an intraoperative image of the distal femur was obtained, transferred to the navigation system and reconstructed into a 3D image. A navigation computer helped the surgeon visualize the entire lateral wall of the femoral notch and lateral intercondylar ridge, even when the remnant of the ruptured ACL impeded arthroscopic visualization of the bone surface. When a guide was placed, the virtual femoral tunnel overlapped the reconstructed 3D image in real time; therefore, only minimal soft tissue debridement was required. Materials and Methods We treated 47 patients with remnant-preserving ACL reconstruction using this system. The center of the femoral socket aperture was calculated according to the quadrant technique using 3D computed tomography imaging. Results The femoral socket locations were considered to be an anatomical footprint in accordance with previous cadaveric studies. Conclusions The 3D fluoroscopy-based navigation can assist surgeons in creating anatomical femoral sockets during remnant-preserving ACL reconstruction.

Iliotibial band irritation caused by the EndoButton after anatomic double-bundle anterior cruciate ligament reconstruction: report of two cases.

Two patients underwent arthroscopic anatomic double-bundle anterior cruciate ligament (ACL) reconstruction using the EndoButton for femoral fixation. The femoral tunnels were created by the inside-out technique through a far anteromedial portal. The patients postoperatively developed moderate lateral knee pain without instability. At the second-look arthroscopic evaluation, the two EndoButtons were removed. Both patients were completely asymptomatic several months after implant removal, implying that the EndoButtons caused the mechanical irritation in the iliotibial band. This is the first report describing removal of EndoButtons because of pain caused by friction with the iliotibial band. In anatomic ACL reconstruction, if the femoral tunnel exit is positioned near the lateral femoral epicondyle, care should be taken to prevent iliotibial band friction syndrome that could result because of the EndoButton.

Stress Fracture of the Anterior Process of the Calcaneus A Case Report

Stress fracture of the anterior process of the calcaneus is rare. We present a case of a 14-year-old female basketball player who suffered a stress fracture of the anterior process of the calcaneus that was not associated with a calcaneonavicular coalition. After conservative treatment failed, drilling of the fracture site was required to facilitate healing. A possible cause of this rare type of stress fracture seemed to be a long anterior process of the calcaneus. Level of Evidence: Therapeutic, Level IV: Case study

Comparison of mouse and human ankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability

OBJECTIVE Prevalence of ankle osteoarthritis (OA) is lower than that of knee OA, however, the molecular mechanisms underlying the difference remain unrevealed. In the present study, we developed mouse ankle OA models for use as tools to investigate pathophysiology of ankle OA and molecular characteristics of ankle cartilage. DESIGN We anatomically and histologically examined ankle and knee joints of C57BL/6 mice, and compared them with human samples. We examined joints of 8-week-old and 25-month-old mice. For experimental models, we developed three different ankle OA models: a medial model, a lateral model, and a bilateral model, by resection of respective structures. OA severity was evaluated 8 weeks after the surgery by safranin O staining, and cartilage degradation in the medial model was sequentially examined. RESULTS Anatomical and histological features of human and mouse ankle joints were comparable. Additionally, the mouse ankle joint was more resistant to cartilage degeneration with aging than the mouse knee joint. In the medial model, the tibiotalar joint was markedly affected while the subtalar joint was less degenerated. In the lateral model, the subtalar joint was mainly affected while the tibiotalar joint was less altered. In the bilateral model, both joints were markedly degenerated. In the time course of the medial model, TdT-mediated dUTP nick end labeling (TUNEL) staining and Adamts5 expression were enhanced at early and middle stages, while Mmp13 expression was gradually increased during the OA development. CONCLUSION Since human and mouse ankles are comparable, the present models will contribute to ankle OA pathophysiology and general cartilage research in future.

An additional reference axis improves femoral rotation alignment in image-free computer navigation assisted total knee arthroplasty.

Few studies have demonstrated improvement in accuracy of rotational alignment using image-free navigation systems mainly due to the inconsistent registration of anatomical landmarks. We have used an image-free navigation for total knee arthroplasty, which adopts the average algorithm between two reference axes (transepicondylar axis and axis perpendicular to the Whiteside axis) for femoral component rotation control. We hypothesized that addition of another axis (condylar twisting axis measured on a preoperative radiograph) would improve the accuracy. One group using the average algorithm (double-axis group) was compared with the other group using another axis to confirm the accuracy of the average algorithm (triple-axis group). Femoral components were more accurately implanted for rotational alignment in the triple-axis group (ideal: triple-axis group 100%, double-axis group 82%, P<0.05).

Regulation of Chondrocyte Survival in Mouse Articular Cartilage by p63

Transcription factor p63, of the p53 family, regulates cell proliferation, survival, and apoptosis in various cells and tissues. This study was undertaken to examine the expression and roles of p63 transcript variants in the mouse growth plate and articular chondrocytes.

p63 Regulates Chondrocyte Survival in Articular Cartilage

Transcription factor p63, of the p53 family, regulates cell proliferation, survival, and apoptosis in various cells and tissues. This study was undertaken to examine the expression and roles of p63 transcript variants in the mouse growth plate and articular chondrocytes.

The role of medial meniscus posterior root tear and proximal tibial morphology in the development of spontaneous osteonecrosis and osteoarthritis of the knee

BACKGROUND Medial meniscus posterior root tear (MMPRT) has been reported to play a key role in the development of spontaneous osteonecrosis of the knee (SONK) and osteoarthritis (OA) of the knee. However, little is known about the differences in the development of SONK and OA after MMPRT. The purpose of this study was to investigate the factors contributing to the development of these conditions. METHODS We evaluated the existence of MMPRT and the extent of medial meniscal extrusion in preoperative magnetic resonance images and proximal tibial morphology in radiographs of 45 patients with SONK and 104 patients with OA who underwent knee surgery. RESULTS There were no significant differences in age, gender, height, weight, and body mass index between the two groups. The incidence of MMPRT and the mean posterior tibial slope (PTS) were significantly higher in SONK than in OA patients (62.2% versus 34.3%, P=0.002, and 12.8° versus 10.5°, P<0.001, respectively). The mean extent of meniscal extrusion was larger in OA than in SONK patients (7.5mm versus 5.3mm, P<0.001). The mean tibial varus angle was 4.8° in SONK and 5.4° in OA, with no significant difference between the two (P=0.088). Multivariable logistic regression analysis showed that compared with OA, SONK was more closely associated with the existence of MMPRT and had a smaller extent of medial meniscus extrusion and higher PTS. CONCLUSION MMRPT and higher PTS were more closely associated with the development of SONK than with that of OA.