Bone-to-bone integrations were complete within 5 months after anatomical rectangular tunnel anterior cruciate ligament reconstruction using a bone-patellar tendon-bone graft.

PURPOSE: Anterior cruciate ligament (ACL) reconstruction using a bone-patellar tendon-bone (BTB) graft is known to provide secure fixation due to the direct bone-to-bone integration of the bone plug and bone tunnel. It is important to know the time required for bone integration when designing the postoperative rehabilitation protocol or deciding when the patient can return to competition-level activity, especially if the patient is an athlete. However, because reports are scarce, the period necessary for bone-to-bone integration after ACL reconstruction using a BTB graft remains unclear. The purpose of this study was to clarify this issue. It was hypothesised that ACL reconstruction using a BTB graft via an anatomical rectangular tunnel would help in the integration between bone plugs and bone tunnels on both the femoral and tibial sides after at least 6 months, at which point basic exercises similar to pre-injury sporting activity levels can be resumed. METHODS: This study included 40 knees treated with ACL reconstruction using a BTB graft via anatomical rectangular tunnel reconstruction between 2013 and 2014 in a single institute. The integration between bone plugs and bone tunnels was evaluated using multi-slice tomosynthesis, which is a technique for producing slice images using conventional radiographic systems, at 1, 3, and 5 months postoperatively. All procedures were performed by two experienced surgeons. Bone integration was evaluated by two orthopaedic doctors. RESULTS: The rates of integration of the bone plug and femoral bone tunnel on tomosynthesis at 1, 3, and 5 months postoperatively were 0, 55, and 100%, respectively. On the tibial side, the corresponding rates were 0, 75, and 100%, respectively. The rate of integration on the tibial side was significantly higher than that on the femoral side at 3 months postoperatively (p = 0.031). CONCLUSIONS: Bone-to-bone integration on the femoral and tibial sides was complete within 5 months after surgery in all cases. Since the time required for bone integration is important in designing the postoperative rehabilitation approach, these results will serve as a useful guideline for planning rehabilitation protocols. LEVEL OF EVIDENCE: IV.

Clinical outcome of anatomic double-bundle ACL reconstruction and 3D CT model-based validation of femoral socket aperture position.

PURPOSE: The purpose of this study was to evaluate the clinical results of anatomic double-bundle (DB) anterior cruciate ligament (ACL) reconstruction in which anatomic position of femoral socket apertures was validated using three-dimensional (3D) computed tomography (CT) modelling. METHODS: Anatomic DB ACL reconstructions with hamstring autografts were performed in 34 patients. Two femoral sockets were created through a far anteromedial (AM) portal behind the lateral intercondylar ridge with the assistance of intraoperative 3D fluoroscopic navigation. Femoral tunnel aperture positioning was investigated postoperatively using 3D CT images in all patients. Clinical results were also evaluated subjectively and objectively at least up to 2 years. RESULTS: Measurement of the AM and the posterolateral (PL) femoral socket locations on the 3D CT images using the quadrant method showed that the centre of the AM socket aperture was located at a depth of 21.0 ± 4.1% and a height of 30.5 ± 9.3% and that of the PL socket aperture was located at a depth of 31.3 ± 5.8% and a height of 57.2 ± 7.7%. The femoral socket locations were considered as anatomic in accordance with previous cadaveric studies examining the positions of ACL femoral insertion site. Subjectively, the mean Lysholm score was 96.9 ± 4.0 points. According to IKDC final objective scores, 26 knees (76%) were objectively graded as normal, 8 (24%) as nearly normal, and 0 (0%) as abnormal or severely abnormal. Postoperative side-to-side anterior translation measured with a KT-2000 arthrometer averaged 0.7 ± 1.2 mm. CONCLUSIONS: DB ACL reconstructions in which femoral socket apertures were validated anatomically using 3D CT provided satisfactory short-term results. LEVEL OF EVIDENCE: Case series, Level IV.

Kinematic Alignment Achieves a More Balanced Total Knee Arthroplasty Than Mechanical Alignment among CPAK Type I Patients: A Simulation Study.

Background: There is no consensus on whether mechanical alignment (MA) or kinematic alignment (KA) should be chosen for total knee arthroplasty (TKA) for coronal plane alignment of the knee (CPAK) Type I with a varus arithmetic HKA (aHKA) and apex distal joint line obliquity (JLO). The aim of this study was to investigate whether MA or KA is preferable for soft tissue balancing in TKA for this phenotype. Method: This prospective cohort study included 64 knees with CPAK Type I osteoarthritis that had undergone cruciate-retaining TKA. Using optical tracking software, we simulated implant placement in the Mako system before making the actual bone cut and compared the results between MA and KA. Extension balance (the difference between medial and lateral gaps in extension) and medial balance (the difference in medial gaps in flexion and extension) were examined. These gap differences within 2 mm were defined as good balance. Achievement of overall balance was defined as an attainment of good extension and medial balance. The incidence of balance in each patient was compared with an independent sample ratio test. Results: Compared with the MA group, the KA group achieved better soft tissue balance in extension balance (p < 0.001). A total of 75% of the patients in the KA group achieved overall balance, which was greater than the 38% achieved in the MA group (p < 0.001). Conclusions: In robot-assisted TKA for CPAK Type I osteoarthritis, KA achieved knee balance during extension without soft tissue release in a greater percentage of patients than MA.

Correction of Varus Alignment with Peripheral Osteophyte Removal during Total Knee Arthroplasty: An Assessment with Computer Navigation.

Techniques for symmetrical balancing in flexion and extension have been described; however, the ideal technique is unclear. This study aimed to clarify whether resection of peripheral osteophytes could restore neutral hip-knee-ankle (HKA) angle of varus deformity of arthritic knees. Data from 90 varus arthritic knees that had undergone total knee arthroplasty (TKA) using a nonimage-based navigation system were analyzed. The change in the coronal mechanical axis, while applying manual valgus stress at extension and 90 degrees of knee flexion, was recorded after the following sequential procedures: (1) anterior cruciate ligament (ACL) sectioning, (2) subperiosteal stripping of the deep medial collateral ligament (MCL) from the underlying osteophytes on the medial tibia, and (3) complete removal of peripheral osteophytes from the proximal medial tibia and distal medial femoral condyle. Repeated measures of analysis of variance (ANOVA) were performed to compare the varus angle among each step, and a post hoc analysis by paired t-test was utilized to compare the parameters between baseline and each step. The varus alignment with valgus stress at extension and 90 degrees of flexion (mean: 6.0 ± 3.6 and 5.2 ± 3.9 degrees of varus, respectively) was significantly corrected to a near-neutral mechanical axis (mean: 0.9 ± 2.4 and 1.4 ± 4.2 degrees of varus, respectively) after peripheral osteophyte resection (p < 0.01, both). In many cases, varus deformity of arthritic knees could be corrected to near-neutral HKA angle by applying manual valgus stress after complete peripheral osteophyte resection. These procedures could facilitate soft tissue balancing in TKA, minimizing the risk of overrelease of the medial soft tissues.

Distribution of Coronal Plane Alignment of the Knee Classification in Patients with Knee Osteoarthritis in Japan.

Coronal plane alignment of the knee (CPAK) has recently been proposed as a simple and universal classification system to determine the suitability of a particular phenotype of the knee to a specific alignment strategy for knee replacement surgery. Although racial differences may affect knee alignment, there are no reports on the racial distribution of this classification system. We aimed to clarify the distribution of CPAK classification in patients with osteoarthritis who underwent total knee arthroplasty (TKA) in Japan. Consecutive patients who underwent primary TKA were analyzed retrospectively. The knees were categorized according to the CPAK classification system which comprised of two independent variables (arithmetic hip-knee-ankle [aHKA] angle and joint-line obliquity [JLO]) with three respective subgroups to create the following nine phenotypes of the knee: type I (varus aHKA and apex distal JLO), type II (neutral aHKA and apex distal JLO), type III (valgus aHKA and apex distal JLO), type IV (varus aHKA and neutral JLO), type V (neutral aHKA and neutral JLO), and type VI (valgus aHKA and neutral JLO), type VII (varus aHKA and apex proximal), type VIII (neutral aHKA and apex proximal), and type IX (valgus aHKA and apex proximal). The distribution of the phenotypes in the Japanese population was investigated as a primary outcome. To accurately compare the results with previous studies conducted on non-Japanese patients, a sex-matched distribution was investigated as a secondary outcome. A total of 570 knees were investigated of which 500 knees were examined after exclusions. The most common distribution was type I (53.8%), followed by type II (25.4%), type III (8.2%), type IV (7.2%), type V (4.4%), and type VI (1.0%). Types VII, VIII, and IX were not distributed. The sex-matched distribution was nearly identical to the overall distribution in Japan. The majority of patients with knee osteoarthritis in Japan had medially tilted joints with constitutional varus alignment.

Distinguishing the proapoptotic and antiresorptive functions of risedronate in murine osteoclasts: role of the Akt pathway and the ERK/Bim axis.

OBJECTIVE: Nitrogen-containing bisphosphonates are one of the most successful therapeutics for osteoporosis. The aim of this study was to elucidate the functional mechanism of one of the typical nitrogen-containing bisphosphonates, risedronate. METHODS: Osteoclasts generated from murine bone marrow macrophages were treated with risedronate in vitro, and its effects on apoptosis and bone-resorbing activity were examined. The mechanism of action of risedronate was examined by gene induction of constitutively active Akt-1 and constitutively active MEK-1, and by gene deletion of Bim. Bim(-/-) mice, in which osteoclasts were resistant to apoptosis, were treated with risedronate and analyzed radiographically, biochemically, and histologically. RESULTS: Risedronate induced osteoclast apoptosis through the mitochondria-dependent pathway with an increased expression of Bim, and the proapoptotic effect of risedronate was suppressed by Bim deletion and constitutively active MEK-1 introduction. In contrast, the risedronate-induced suppression of bone resorption was completely reversed by inducing constitutively active Akt-1, but not by Bim deletion or constitutively active MEK-1 introduction. These results suggested that apoptosis and bone-resorbing activity of osteoclasts were regulated through the ERK/Bim axis and the Akt pathway, respectively, both of which were suppressed by risedronate. Although osteoclast apoptosis in response to risedronate administration was suppressed in the Bim(-/-) mice, risedronate treatment increased bone mineral density in Bim(-/-) mice at a level equivalent to that in wild-type mice. CONCLUSION: Our findings indicate that the antiresorptive effect of risedronate in vivo is mainly mediated by the suppression of the bone-resorbing activity of osteoclasts and not by the induction of osteoclast apoptosis.

Assessing the Role of Minimal Medial Tissue Release during Navigation-Assisted Varus Total Knee Arthroplasty Based on the Degree of Preoperative Varus Deformity.

We assessed the impact of a minimal medial soft-tissue release with complete peripheral osteophyte removal on the ability to attain manual preresection deformity correction during navigation-assisted total knee arthroplasty (TKA) for varus osteoarthritis. We included 131 TKAs for 109 patients with medial compartment predominant osteoarthritis. The steps for achieving minimal medial soft-tissue release were performed as follows: (1) elevation of a periosteal sleeve to 5-mm distal to the joint line and (2) complete removal of peripheral osteophytes. The evaluation criteria of this study were as follows: (1) age, (2) height, (3) weight, (4) body mass index (BMI), (5) sex, (6) the preoperative femorotibial mechanical angle in the neutral position before medial release and (7) the mechanical angle in maximum manual valgus stress after the two-step medial-release procedure (measured on the navigation screens). Multiple regression analysis of the criteria was performed to determine the degree of varus deformity that allowed neutral alignment but required extensive medial release. The femorotibial mechanical angle in the neutral position before medial release and sex correlated with the mechanical angle in maximum manual valgus stress on the navigation screen after medial release (r = 0.72, p < 0.001). Based on the regression formula, the maximum degree of preoperative varus deformity that allowed neutral alignment by the minimum medial-release procedure was 5.3 degrees for males and 9.1 degrees for females. The magnitude of deformity which has an impact on the ability to correct varus deformity (by minimal soft-tissue release and complete osteophyte removal) was clarified. If the preoperative degree of varus deformity was within 5.3 degrees for males and 9.1 degrees for females, an extensive medial release was not required to obtain neutral alignment.

Postoperative laxity of the lateral soft tissue is largely negligible in total knee arthroplasty for varus osteoarthritis.

PURPOSE: To evaluate the integrity of lateral soft tissue in varus osteoarthritis knee by comparing the mechanical axis under varus stress during navigation-assisted total knee arthroplasty before and after compensating for a bone defect with the implant. METHODS: Sixty-six knees that underwent total knee arthroplasty were investigated. The mechanical axis of the operated knee was evaluated under manual varus stress immediately after knee exposure and after navigation-assisted implantation. The correlation between each value of the mechanical axis and degree of preoperative varus deformity was compared by regression analysis. RESULTS: The maximum mechanical axis under varus stress immediately after knee exposure increased in proportion to the degree of preoperative varus deformity. Moreover, the maximum mechanical axis under varus stress after implantation increased in proportion to the degree of preoperative varus deformity. Therefore, the severity of varus knee deformity leads to a progressive laxity of the lateral soft tissue. However, regression coefficients after implantation were much smaller than those measured immediately after knee exposure (0.99 vs 0.20). Based on the results of the regression formula, the postoperative laxity of the lateral soft tissue was negligible, provided that an appropriate thickness of the implant was compensated for the bone and cartilage defect in the medial compartment without changing the joint line. CONCLUSION: The severity of varus knee deformity leads to a progressive laxity of the lateral soft tissue. However, even if the degree of preoperative varus deformity is severe, most cases may not require additional procedures to address the residual lateral laxity.

Preoperative Magnetic Resonance Imaging as a Diagnostic Aid for Hypermobile Lateral Meniscus.

BACKGROUND: Hypermobile lateral meniscus is difficult to diagnose with imaging due to its absence of tears or anomalies. We aimed to clarify the accuracy of the preoperative diagnosis using magnetic resonance imaging (MRI). METHODS: The preoperative MRI status of the posterosuperior popliteomeniscal fascicle (sPMF), anteroinferior popliteomeniscal fascicle (iPMF), and popliteal hiatus were examined retrospectively on sagittal images in the hypermobile lateral meniscus group (n = 22) and an age- and gender-matched control group (n = 44). These statuses were evaluated by a logistic regression analysis to assess their degree of diagnostic accuracy. RESULTS: The area under the curve (AUC) of the sPMF, iPMF, popliteal hiatus, and all three criteria combined was 0.66, 0.74, 0.64, and 0.77, respectively (low, moderate, low, and moderate accuracy, respectively). The odds ratios of the most severe type 3 forms of the sPMF, iPMF, and popliteal hiatus for hypermobile lateral meniscus were significantly high (5.50, 12.20, and 5.00, respectively). Although the diagnostic accuracy was not high enough, the significantly higher odds ratio for type 3 may indicate a hypermobile lateral meniscus. CONCLUSION: a definitive diagnosis of hypermobile lateral meniscus is difficult with MRI findings alone; however, MRI evaluations of the iPMF, sPMF, and the widening of popliteal hiatus can be used as an adjunct to diagnosis.

Tomosynthesis Is Equivalent to Computed Tomography for Evaluating Osseous Integration After Anterior Cruciate Ligament Reconstruction.

PURPOSE: To compare tomosynthesis and computed tomography (CT) for evaluating bone plug integration after anterior cruciate ligament (ACL) reconstruction with a bone-patellar tendon-bone (BPTB) graft. METHODS: Data of consecutive adult patients who underwent ACL reconstruction with BPTB were analyzed. Bone integration between the bone plug and bone tunnel was evaluated by tomosynthesis and CT, which were both performed 3 months postoperatively. The obtained data for both modalities were reconstructed with slice thickness of 2 mm. Evaluation of bone integration were separately performed using coronal- and sagittal-reconstructed images for the femur and tibia. The ratio of bone integration between the reconstructed slices in which bone grafting was involved, for both tomosynthesis and CT, was investigated by 2 blinded examiners. The equivalence of tomosynthesis to CT was tested by comparing the bone integration ratio for both modalities. The accuracy of diagnosing bone union using tomosynthesis and CT was also investigated. RESULTS: The diagnostic accuracy of tomosynthesis and CT exceeded 80%. Interobserver agreement of bone integration in the sagittal plane on the femoral side was 0.92 (intraclass correlation coefficient) for CT and 0.76 (intraclass correlation coefficient) for tomosynthesis. CONCLUSIONS: Although it showed poor reliability, tomosynthesis was equivalent to CT in evaluating bone plug integration after ACL reconstruction with BPTB. LEVEL OF EVIDENCE: Level II, diagnostic study.

[Drugs under development for osteoporosis ].

Osteoporosis is a disease in which the density and quality of bone is reduced, leading to an increase in fragility fractures. Osteoporosis is a major health threat affecting more than 10 million people in Japan. Emerging evidence has shown that anti-resorptive drugs such as bisphosphonates and raloxifene efficiently increase bone mass and prevent osteoporotic fractures by maintaining bone homeostasis. In addition, anabolic drugs such as parathyroid hormone and novel anti-resorptive drugs such as anti-RANKL drugs and cathepsin K inhibitors, which directly target osteoclasts are under development. In this review, we would like to summarize the current status of the development of anti-osteoporotic drugs.

Secure fixation of femoral bone plug with a suspensory button in anatomical anterior cruciate ligament reconstruction with bone-patellar tendon-bone graft.

PURPOSE: the efficacy and safety of using a suspensory button for femoral fixation in anatomical anterior cruciate ligament (ACL) reconstruction with bone-patellar tendon-bone (BPTB) graft have not been established. The purpose of the current study was to evaluate bone plug integration onto the femoral socket and migration of the bone plug and the EndoButton (EB) (Smith & Nephew, Andover, MA, USA) after rectangular tunnel ACL reconstruction with BPTB autograft. METHODS: thirty-four patients who underwent anatomical rectangular ACL reconstruction with BPTB graft using EB for femoral fixation and in whom three-dimensional (3D) computed tomography (CT) was performed one week and one year after surgery were included in this study. Bone plug integration onto the femoral socket, bone plug migration, soft tissue interposition, EB migration and EB rotation were evaluated on 3D CT. The clinical outcome was also assessed and correlated with the imaging outcomes. RESULTS: the bone plug was integrated onto the femoral socket in all cases. The incidence of bone plug migration, soft tissue interposition, EB migration and EB rotation was 15, 15, 9 and 56%, respectively. No significant association was observed between the imaging outcomes. The postoperative mean Lysholm score was 97.1 ± 5.0 points. The postoperative side-to-side difference, evaluated using a KT-2000 arthrometer, averaged 0.5 ± 1.3 mm. There were no complications associated with EB use. Imaging outcomes did not affect the postoperative KT side-to-side difference. CONCLUSIONS: the EB is considered a reliable device for femoral fixation in anatomical rectangular tunnel ACL reconstruction with BPTB autograft. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Individual and combining effects of anti-RANKL monoclonal antibody and teriparatide in ovariectomized mice.

We examined the individual and combined effects of teriparatide and anti-RANKL (receptor activator of nuclear factor κB ligand) monoclonal antibody in ovariectomized mice. Three-month-old female C57BL/6 mice were ovariectomized (OVX) or sham operated. Four weeks after OVX, they were assigned to 3 different groups to receive anti-RANKL monoclonal antibody (Ab) alone (5 mg/kg single injection at 4 weeks after OVX, Ab group), teriparatide alone (80 µg/kg daily injection for 4 weeks from 4 weeks after OVX, PTH group), or mAb plus teriparatide (Ab + PTH group). Mice were sacrificed 8 weeks after OVX. Bone mineral density (BMD) was measured at the femur and lumbar spine. Hind limbs were subjected to histological and histomorphometric analysis. Serum osteocalcin and CTX-I levels were measured to investigate the bone turnover. Compared with Ab group, Ab + PTH group showed a significant increase in BMD at distal femur and femoral shaft. Cortical bone volume was significantly increased in PTH and Ab + PTH groups compared with Ab group. Bone turnover in Ab + PTH group was suppressed to the same degree as in Ab group. The number of TRAP-positive multinucleated cells was markedly reduced in Ab and Ab + PTH groups. These results suggest that combined treatment of teriparatide with anti-RANKL antibody has additive effects on BMD in OVX mice compared with individual treatment.

Genomewide comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced osteoclastogenesis.

We have previously reported that transforming growth factor ß (TGF-ß) plays an essential role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the detailed underlying molecular mechanisms still remain unclear. Formaldehyde-assisted isolation of regulatory elements (FAIRE) and chromatin immunoprecipitation (ChIP) followed by sequencing (FAIRE-seq and ChIP-seq) analyses indicated the cooperation of Smad2/3 with c-Fos during osteoclastogenesis. Biochemical analysis and immunocytochemical analysis revealed that physical interaction between Smad2/3 and c-Fos is required for their nuclear translocation. The gene expression of nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1), a key regulator of osteoclastogenesis, was regulated by RANKL and TGF-ß, and c-Fos binding to open chromatin sites was suppressed by inhibition of TGF-ß signaling by SB431542. Conversely, Smad2/3 binding to Nfatc1 was impaired by c-Fos deficiency. These results suggest that TGF-ß regulates RANKL-induced osteoclastogenesis through reciprocal cooperation between Smad2/3 and c-Fos.

Anti-apoptotic Bcl-2 family member Mcl-1 regulates cell viability and bone-resorbing activity of osteoclasts.

Myeloid cell leukemia sequence 1 (Mcl-1) is an anti-apoptotic Bcl-2 family protein and an immediate early gene expressed during myeloid leukemia cell line differentiation. We analyzed the expression and function of Mcl-1 in osteoclasts. Mcl-1 protein exhibited a short half-life in osteoclasts caused by its degradation in the ubiquitin-proteasome system. Mcl-1 had no effect on osteoclast differentiation, but its overexpression prolonged osteoclast survival and suppressed the bone-resorbing activity of these cells, as determined by pit formation assay. Conversely, Mcl-1 depletion suppressed osteoclast survival and increased bone resorption. This negative role for Mcl-1 on the bone-resorptive activities of osteoclasts may be caused by the increase in adenosine triphosphate/adenosine diphosphate ratio. Finally, we showed that the local deletion of Mcl-1 by the injection of the Cre adenovirus into the calvaria of Mcl1(fl/fl) mice significantly affected GST-RANKL-induced bone resorption in vivo. These results demonstrated that Mcl-1 positively regulates cell viability and negatively regulates the bone-resorbing activity of osteoclasts both in vitro and in vivo.

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.

Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5-Dusp axis in the osteoclast.

Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal-related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.

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.

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B-mediated vesicle transport.

Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptors and regulate a wide range of cellular processes. In osteoclasts, they are activated downstream of α(v) ß(3) integrin and colony-stimulating factor-1 receptor (c-Fms), which are involved in the regulation of bone-resorbing activity. The physiological relevance of the in vitro studies using PI3K inhibitors has been of limited value, because they inhibit all classes of PI3K. Here, we show that the osteoclast-specific deletion of the p85 genes encoding the regulatory subunit of the class IA PI3K results in an osteopetrotic phenotype caused by a defect in the bone-resorbing activity of osteoclasts. Class IA PI3K is required for the ruffled border formation and vesicular transport, but not for the formation of the sealing zone. p85α/ß doubly deficient osteoclasts had a defect in macrophage colony-stimulating factor (M-CSF)-induced protein kinase B (Akt) activation and the introduction of constitutively active Akt recovered the bone-resorbing activity. Thus, the class IA PI3K-Akt pathway regulates the cellular machinery crucial for osteoclastic bone resorption, and may provide a molecular basis for therapeutic strategies against bone diseases.

Regulation of RANKL-induced osteoclastogenesis by TGF-ß through molecular interaction between Smad3 and Traf6.

Previous studies have shown that transforming growth factor ß (TGF-ß) promotes receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the underlying molecular mechanisms have not been elucidated. When TGF-ß signals were blocked either by a specific inhibitor of TGF-ß type 1 receptor kinase activity, SB431542, or by introducing a dominant-negative mutant of TGF-ß type 2 receptor, RANKL-induced osteoclastogenesis was almost completely suppressed. Blockade of Smad signaling by overexpression of Smad7 or c-Ski markedly suppressed RANKL-induced osteoclastogenesis, and retroviral induction of an activated mutant of Smad2 or Smad3 reversed the inhibitory effect of SB431542. Immunoprecipitation analysis revealed that Smad2/3 directly associates with the TRAF6-TAB1-TAK1 molecular complex, which is generated in response to RANKL stimulation and plays an essential role in osteoclast differentiation. TRAF6-TAB1-TAK1 complex formation was not observed when TGF-ß signaling was blocked. Analysis using deletion mutants revealed that the MH2 domain of Smad3 is necessary for TRAF6-TAB1-TAK1 complex formation, downstream signal transduction, and osteoclast formation. In addition, gene silencing of Smad3 in osteoclast precursors markedly suppressed RANKL-induced osteoclast differentiation. In summary, TGF-ß is indispensable in RANKL-induced osteoclastogenesis, and the binding of Smad3 to the TRAF6-TAB1-TAK1 complex is crucial for RANKL-induced osteoclastogenic signaling.