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Introduction: Hansson Pinloc system consists of three pins locking into a plate. In biomechanical trials, the novel plate design with its pin configuration enhanced torsional stability. Hansson Pinloc has been used for femoral neck fracture in some countries including Sweden and Japan. Recently, the outcome of a randomized clinical study comparing Hansson Pinloc and conventional Hansson pins was published. However, subtrochanteric fracture after internal fixation using Hansson Pinloc has not been reported in the English literature including the above report. Only several Japanese literatures reported some cases with this post-operative complication. We present a case with subtrochanteric fracture after internal fixation using Hansson Pinloc. Case Report: Subtrochanteric fractures after internal fixation of femoral neck fractures are rare but severe complications. We present our experience of this complication after internal fixation using Hansson Pinloc system which is a new design implant for femoral neck fracture. A 67-year-old woman was diagnosed with a femoral neck fracture of Garden stage I after a fall. She underwent closed reduction and internal fixation using Hansson Pinloc system. At 4 weeks after surgery, she suffered subtrochanteric fracture without any episode of trauma. The patient underwent removal of the instrumentation and internal fixation with a long femoral nail. We get in trouble with removing Hansson Pinloc system due to secondary fracture, and of bone defect. 9 weeks after the second surgery, the patient could get bone union and walk using double T-canes. Conclusion: Surgeons should be cognizant of this post-operative complication before using this system. In osteosynthesis of the femoral neck fracture using Hansson Pinloc, we should keep in mind that subtrochanteric fracture is a possible post-operative complication. Keywords: Femoral neck fracture, Osteosynthesis, Post-operative complication, Subtrochanteric fracture

Spinal cord injury (SCI) causes motor and sensory deficits and is currently considered an incurable disease. We have previously reported that administration of anti-High Mobility Group Box-1 monoclonal antibody (anti-HMGB1 mAb) preserved lesion area and improved locomotion recovery in mouse model of SCI. In order to further enhance the recovery, we here examined combinatorial treatment of anti-HMGB1 mAb and epothilone B (Epo B), which has been reported to promote axon regeneration. This combinatorial treatment significantly increased hindlimb movement compared with anti-HMGB1 mAb alone, although Epo B alone failed to increase functional recovery. These results are in agreement with that anti-HMGB1 mAb alone was able to decrease the lesion area spreading and increase the surviving neuron numbers around the lesion, whereas Epo B facilitated axon outgrowth only in combination with anti-HMGB1 mAb, suggesting that anti-HMGB1 mAb-dependent tissue preservation is necessary for Epo B to exhibit its therapeutic effect. Taken together, the combinatorial treatment can be considered as a novel and clinically applicable strategy for SCI.

Pseudoaneurysms of the peroneal artery around the ankle joint have rarely been reported. We present the case of a 64-year-old man with a pseudoaneurysm of the anterior perforating branch of the peroneal artery associated with a screw inserted from the anterolateral distal tibia during ankle arthrodesis. Endovascular treatment with selective catheterization and coil embolization was successfully performed. The ankle joint achieved bone union without delay, and the pseudoaneurysm did not recur at the 18-month follow-up.This is the first report describing a pseudoaneurysm of the peroneal artery after ankle arthrodesis. Successful outcomes can be achieved by endovascular treatment.

Background:Resection arthroplasty has long been a major treatment option for forefoot deformity caused by rheumatoid arthritis (RA). However, metatarsophalangeal (MTP) joint–preserving surgery is now surpassing classic resection arthroplasty. This study was performed to compare the postoperative results of these 2 operative methods.Methods:Fifty-one toes of 40 patients with RA who underwent resection arthroplasty (resection group) or MTP joint–preserving arthroplasty (preservation group) from 2014 to 2017 for forefoot deformity were followed up for >1 year and were retrospectively analyzed. In the preservation group, open reduction of joint dislocation was performed if needed, and the deformity was corrected by metatarsal shortening osteotomy. The mean follow-up period was 21 months. The Japanese Society for Surgery of the Foot (JSSF) scales (objective outcome measures), the Self-Administered Foot Evaluation Questionnaire (SAFE-Q) (subjective outcome measure), and radiographic indices were compared between the groups. The resection group and preservation group comprised 15 toes of 11 patients and 36 toes of 29 patients, respectively.Results:There were no significant differences in the preoperative radiographic indices, JSSF scales, or SAFE-Q results between the 2 groups. The preservation group showed better JSSF scores at the last follow-up (median hallux scale, 89 vs 74; median lesser scale, 87 vs 79). In the preservation group, the SAFE-Q scores gradually improved with time until 12 months postoperatively. In the resection group, the scores decreased 3 months postoperatively and then improved and reached a plateau 6 months postoperatively. At 12 months postoperatively, there was no significant difference in the SAFE-Q scores between the 2 groups.Conclusions:MTP joint–preserving arthroplasty resulted in superior objective scores to resection arthroplasty in patients with RA forefoot deformity. Although the subjective scores did not differ between the groups at the last follow-up, the time course of postoperative quality of life improvement was different between the 2 surgeries.Level of Evidence:Level III, retrospective comparative study.

Background The purpose of this study was to clarify the clinical outcomes of surgical treatment for end-stage ankle osteoarthritis in patients aged ≥75 years and compare the outcomes with those of patients aged

Objectives The purpose of this study was to clarify the prevalence of pain outside the foot, and to determine the associations of pain outside the foot with foot-specific quality of life (QOL) in patients with hallux valgus. Methods Patients scheduled to undergo hallux valgus surgery were recruited. Patients answered whether they experienced disabling pain in 13 body regions other than the foot. Foot-specific QOLwas assessed using the Self-Administered Foot Evaluation questionnaire (SAFE-Q). Foot pain was quantified using the visual analogue scale (VAS). Patient characteristics, including age, sex, comorbidity, anxiety, and depression, were also surveyed. The association between pain elsewhere and the SAFE-Q and pain VAS scores were assessed using univariate and multivariate analyses. Results Of 102 patients, 55 (54%) experienced pain other than the foot. All SAFE-Q subscale scores were lower, and pain VAS was higher in patients with pain elsewhere than in patients without. In the multivariate analysis, an increase in the number of pain regions was independently associated with a decrease in SAFE-Q scores and an increase in pain VAS. Conclusion More than half of the patients with hallux valgus experienced pain elsewhere. The presence of pain elsewhere was associated with poorer foot-specific QOL and severer foot pain.

CASE Gnathodiaphyseal dysplasia is a generalized skeletal syndrome characterized by frequent bone fractures in childhood, sclerosis and bowing of tubular bones, and cemento-osseous lesions of the jawbones. We present the case of a 53-year-old man with gnathodiaphyseal dysplasia who presented with pathological fracture of the tibial shaft. Internal fixation with the Ender nail was successfully performed with 2 years of follow-up. CONCLUSION This is the first report describing the treatment of fracture in an adult patient with gnathodiaphyseal dysplasia. Internal fixation with the Ender nail was effective for the tubular bone with deformity. Callus formation was observed without delay.

The purpose of this study was to clarify the effect of disease activity on recurrent deformities after resection arthroplasty for forefoot deformities in patients with rheumatoid arthritis (RA).This study included 83 feet in 58 patients with RA who underwent resection arthroplasty of all metatarsal heads, with a minimum follow-up of 2 years. The patients' demographic characteristics, preoperative radiographic findings, and RA disease activity evaluated using the 28-joint disease activity score based on the erythrocyte sedimentation rate (determined preoperatively and at the final follow-up) were compared between feet with and without postoperative recurrent deformities of the toes. Recurrent deformities were assessed separately for the hallux and lesser toes.Recurrence in the hallux and lesser toes occurred in 23 feet (27.7%) and 13 feet (15.7%), respectively. With respect to recurrent hallux deformity, only the preoperative severity of hallux deformity was associated with recurrence. On the other hand, postoperative deformity of the lesser toes was positively associated with disease activity alone and not with other preoperative factors.Postoperative control of RA disease activity was associated with recurrent deformity of the lesser toes but not that of the hallux after resection arthroplasty of all metatarsals for rheumatoid forefoot deformities.

Receptor activator of nuclear factor κB ligand (RANKL) induces osteoclast (OC) differentiation from bone marrow-derived macrophages (BMMs). The transcription factors nuclear factor of activated T cells 1 (NFATc1) and interferon regulatory factor (IRF) 8 play positive and negative roles, respectively, in this process. However, genomewide mapping of the active cis-regulatory elements regulating OC differentiation has not been performed, and little is known about the global landscape of OC-specific gene regulation. We used chromatin immunoprecipitation and formaldehyde-assisted isolation of regulatory elements followed by sequencing to show that PU.1 transcription factor binding motifs were overrepresented at active cis-regulatory regions in both murine BMMs and OCs, while IRF and NFAT binding motifs were selectively enriched at these regions in BMMs and OCs, respectively. We also found that RANKL induced the downregulation of Irf8 and upregulation of Nfatc1 expression, which was associated with dramatic alterations in histone modification. BMM-specific PU.1 binding sites were observed to overlap with IRF8 binding sites in BMMs, and this also occurred for OC-specific PU.1 binding sites and NFATc1 binding sites in OCs. The expression of genes with IRF8 peaks within BMM-specific PU.1 binding sites was significantly higher in BMMs than in OCs, while that of genes with NFATc1 peaks within OC-specific PU.1 binding sites was significantly higher in OCs than in BMMs. Our results suggest that PU.1 switches its transcription partner from IRF8 to NFATc1 and alters the binding regions during RANKL-induced osteoclastogenesis, which is associated with changes in epigenetic profiles and the control of cell type-specific gene expression. © 2019 American Society for Bone and Mineral Research.

The objective of this study was to quantitatively evaluate the effects of daily teriparatide on rheumatoid arthritis patients using predicted bone strength (PBS) assessed by quantitative computed tomography-based finite-element analysis (QCT/FEA) and using bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA), and to prospectively investigate clinical determinants associated with PBS and BMD increases. Participants comprised 39 patients (mean age, 69 years; disease activity score assessing 28 joints with CRP, 3.0; previous vertebral fractures, 82%) enrolled in this study. BMD by DXA and PBS by QCT/FEA of lumbar spine (LS) and proximal femur were measured at baseline, and after 6 and 12 months. In the groups showing increases in these values, variables that may have affected these increases were evaluated using univariate logistic regression analysis. Daily teriparatide treatment significantly increased not only LS BMD, but also LS PBS in RA patients with osteoporosis after both 6 and 12 months of treatment. Increases in N-terminal type I procollagen propeptide (PINP) at 1 and 3 months were significantly associated with increased LS PBS at 12 months according to univariate logistic regression analysis. The threshold value for increased PINP at 1 month for increased PBS at 12 months was 75 µg/L. Increased LS PBS at 12 months was predicted by increased PINP at 1 month from baseline.

Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI.

Injury to the spinal cord causes transection of axon fibers and neural cell death, resulting in disruption of the neural network and severe functional loss. Reconstruction of the damaged neural circuits was once considered to be hopeless as the adult mammalian central nervous system has very poor ability to regenerate. For this reason, there is currently no effective therapeutic treatment for spinal cord injury (SCI). However, with recent developments in stem cell research and cell culture technology, regenerative therapy using neural stem cell (NSC) transplantation has rapidly been developed, and this therapeutic strategy makes it possible to rebuild the destroyed neural circuits. In this review, we discuss the recent breakthroughs in NSC transplantation therapy for SCI. Developmental Dynamics 247:75-84, 2018. © 2017 Wiley Periodicals, Inc.

Although a relationship between joint destruction and functional disorders seems apparent in patients with rheumatoid arthritis (RA), it has not been well proven in the literature. The aims of this study were to clarify the relationship between roentgenographic joint destruction in the hands and functional disorders in patients with RA, and to explore the appropriate assessment measures for functional disorders.Cross-sectional data of the Genant-modified Total Sharp Score (Genant-mTSS), Health Assessment Questionnaire-Disability Index (HAQ-DI), Disabilities of the Arm, Shoulder, and Hand (DASH), and Michigan Hand Outcomes Questionnaire (MHQ) were collected from 50 consecutive RA patients and analyzed.HAQ-DI, DASH, and MHQ had close correlations with Genant-mTSS, with correlation coefficients of 0.69, 0.71, and -0.70, respectively, among patients with low disease activity (DAS28 3.2). A floor effect was observed in HAQ-DI, but neither floor nor ceiling effects were observed in DASH and MHQ. Both DASH and MHQ were strongly correlated with HAQ-DI, with correlation coefficients of 0.87 and 0.73, respectively.Functional disorders had significant relationships with roentgenographic joint destruction in the hands among RA patients with low disease activity. As assessment measures of functional disorders, DASH and MHQ had no floor or ceiling effects, being different from HAQ-DI.

Idiopathic osteonecrosis of the talus is a rare but severe condition that directly affects the ability to walk and is difficult to treat either conservatively or surgically. We report the case of a 72-year-old female with idiopathic necrosis of the talus treated with total talar replacement surgery. A custom-made aluminum-ceramic total talar prosthesis was prepared using the mirror image of the computed tomography and radiographic data from the contralateral ankle. The talus was exposed and removed using an anterior approach, and the total talar prosthesis was inserted. The prosthesis was placed in a stable position between the tibia, calcaneus, and navicular, with no signs of instability with ankle joint movement. The ankle was immobilized in a short-leg cast for 3 weeks. At the latest follow-up examination, 2 years after surgery, the patient was walking without pain. Examination of the left ankle showed 20° of dorsiflexion and 40° of plantar flexion. The American Orthopaedic Foot and Ankle Society ankle/hindfoot score was 90, which had improved from a preoperative score of 45. Radiographic examination showed that the prosthesis was in a stable position in the ankle mortise, and no degenerative or destructive changes were observed in the surrounding bones. This is the first reported case of total talar replacement with a prosthesis for idiopathic talar necrosis. Although the long-term outcome is still unknown, this procedure could provide a good treatment option for idiopathic necrosis of the talus.

Summary 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.

The central nervous system (CNS) is composed of three major cell types, neurons, astrocytes, and oligodendrocytes, which differentiate from common multipotent neural stem/precursor cells (NS/PCs). However, NS/PCs do not have this multipotentiality from the beginning: neurons are generated first and astrocytes are later during CNS development. This developmental progression is observed in vitro by using human (h) NS/PCs derived from pluripotent cells, such as embryonic- and induced pluripotent-stem cells (ES/iPSCs), however, in contrast to rodent's pluripotent cells, they require quite long time to obtain astrocytic differentiation potential. Here, we show that hypoxia confers astrocytic differentiation potential on hNS/PCs through epigenetic alteration for gene regulation. Furthermore, we found that these molecular mechanisms can be applied to functional analysis of patient' iPSC-derived astrocytes. In this review, we summarize recent findings that address molecular mechanisms of epigenetic and transcription factor-mediated regulation that specify NS/PC fate and the development of potential therapeutic strategies for treating astrocyte-mediated neurological disorders.

OBJECTIVES: To evaluate the effects of chronic kidney disease (CKD) and hemodialysis (HD) on the inner ear using the G width (the width between the bimodal peaks of the conductance (G) tympanogram at 2,000 Hz), which reflects the inner ear pressure and/or the existence of endolymphatic hydrops. MATERIALS AND METHODS: We selected five patients (10 ears) from the patients with CKD who were hospitalized for creation of arteriovenous fistula prior to initiation of HD (non-HD group), and we selected seven patients (14 ears) from the patients with CKD who were undergoing HD (the HD group). As a control group, we selected 80 healthy individuals (160 ears); these were mainly the medical staff of the hospital. We measured the G width of the control group and that of patients with CKD using multifrequency tympanometry. RESULTS: The mean G widths of the HD (measured just before an HD session), non-HD, and control groups were 210.7, 128.4, and 97.0 daPa, respectively. The G width of the HD group was significantly greater than that of the control and non-HD groups (p

To investigate the effect of bilateral and unilateral joint disease on the Modified Health Assessment Questionnaire (MHAQ) scores and the differences in joint weighting in rheumatoid arthritis patients.A total of 9212 subjects from the Japanese nationwide cohort database NinJa, 2011, were analyzed. The presence or absence of disease in each joint, including swelling and/or tenderness, was investigated. The correlations between bilateral and unilateral disease in each joint and MHAQ scores were investigated using multivariable logistic regression analysis.The patients' mean age and disease duration was 63.2 and 12.2 years, respectively. The Disease Activity Score-28 was 3.3. The odds ratios of physical impairment according to the MHAQ using multivariable logistic regression models for bilateral and unilateral joints, respectively, were: shoulder, 4.0 and 1.8; elbow, 2.6 and 1.8; wrist, 1.9 and 1.5; hip, 1.7 and 3.0; knee, 2.6 and 1.9; ankle, 2.3 and 2.0, finger, 1.4 and 1.2; and toe, 1.0 and 1.1. The shoulder, elbow, wrist, knee, and ankle had a significant effect on physical impairment.The MHAQ score was significantly affected by shoulder, elbow, wrist, knee, and ankle joint disease. Furthermore, bilateral disease tended to have a greater effect on physical impairment than unilateral disease.

The aim of this study was to clarify the prevalence and the predictive factors for undergoing total knee arthroplasty (TKA) among patients with rheumatoid arthritis (RA).The data of 1,134 patients with RA who were enrolled in the Japanese nationwide cohort database NinJa in 2003 and consecutively followed up until 2009 were analyzed.Seventy-six patients underwent TKA during the observation period. The yearly progression of the modified Health Assessment Questionnaire or mHAQ score from 2003 to 2004, but not the yearly progression of the Disease Activity Score in 28 Joints or DAS28 or patient visual analog scale (VAS) score, was significantly higher in the patients who underwent TKA than those who did not. Multivariate analysis showed that knee involvement in the disease, high Steinbrocker stage (III or IV), and high patient VAS score at the time of enrollment were powerful predictive factors, with hazard ratios of 4.01, 3.71, and 1.20, respectively. According to survival analysis with TKA as an endpoint, patients with knee involvement in the disease at the time of enrollment had a significantly worse 5-year survival rate than did those without knee involvement (83.5% vs. 97.0%, respectively).Several factors were elucidated as predictive factors for undergoing TKA among patients with RA.

We herein report a case of posterior semicircular canal dehiscence (SCD) syndrome who had been audiologically followed up for eight years. The patient originally had sensorineural hearing loss. The audiogram had gradually transformed to pure conductive hearing loss. The posterior SCD was identified in CT scan. The reported case showed the possibility to distinguish the mechanism at play underlying the typical conductive hearing loss in SCD patients by tracing the transition of the hearing loss pattern. This information is of much help to predict the hearing outcomes if surgical intervention were chosen for the treatment.

Objective:To investigate the characteristic physical properties of the oscillating system in the intact middle ear using a high-speed camera.Design:We analysed the oscillation of the guinea pig stapes using a high-speed camera. The specimens were prepared so that the middle-ear structures were intact. Tones of various frequencies were delivered into the external auditory canal.Results:We found that the stapes showed a damped oscillation after the sound stimulation had stopped. The damped oscillation after the sound stimulation showed a specimen-specific frequency that was independent of the frequency of the stimulating sound. An injury to the bony labyrinth, which removed most of the mass from the oscillating system, attenuated the damped oscillation. Therefore, this damped oscillation is likely a passive motion, rather than a reverberation of the stimulating sound.Conclusion:Analysing the passive damped oscillation may reveal the characteristic physical properties of the oscillating system in the near-intact middle ear. Further refinement of this simple and straightforward system may enhance basic and clinical research on the middle ear in a more intuitive way.

To evaluate the prevention of knee joint destruction and clinical efficacy of methotrexate (MTX) plus etanercept (ETN) compared with MTX monotherapy in patients with rheumatoid arthritis (RA) by using semi-automated software for magnetic resonance imaging (MRI) scan analysis.This study enrolled patients with active moderate-to-severe RA who displayed an inadequate response to oral MTX at screening. Patients were assigned to receive either MTX plus ETN or MTX monotherapy (≥10 mg/week). The primary endpoint was the quantitative knee cartilage volume using our software developed for MRI scan analysis.A total of 18 female patients were enrolled in this study and allocated to the MTX + ETN group (n = 9) or the MTX monotherapy group (n = 9). At 52 weeks, the quantitative knee cartilage volume was significantly reduced compared with baseline in both groups (MTX plus ETN group: 2.3 ± 2.3 cmThe semi-automated software for MRI scan analysis can reveal useful and potentially clinically important information about the characteristics of knee joint destruction in patients with RA.

Injury to the spinal cord causes transection of axon fibers and neural cell death, resulting in disruption of the neural network and severe functional loss. Reconstruction of the damaged neural circuits was once considered to be hopeless as the adult mammalian central nervous system has very poor ability to regenerate. For this reason, there is currently no effective therapeutic treatment for spinal cord injury (SCI). However, with recent developments in stem cell research and cell culture technology, regenerative therapy using neural stem cell (NSC) transplantation has rapidly been developed, and this therapeutic strategy makes it possible to rebuild the destroyed neural circuits. In this review, we discuss the recent breakthroughs in NSC transplantation therapy for SCI. Developmental Dynamics 247:75-84, 2018. © 2017 Wiley Periodicals, Inc.

Case Stiff-person syndrome is a rare neurological disorder characterized by rigidity and painful spasms of the trunk and limbs, and patients sometimes have difficulty in walking due to rigid toe deformities. This is a case report of a 76-year-old woman suffering from stiff-person syndrome with painful rigid toe deformities regained walking ability after metatarsal osteotomy and cutting of the toe extensors for all toes in the left foot. Conclusion For patients with stiff-person syndrome, surgical intervention is a powerful treatment option when they have developed rigid and painful toe deformities despite adequate pharmacological treatment.

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.

We investigated the role of protein kinase B (Akt), a downstream effector of phosphatidylinositol 3-kinase, in bone-resorbing activity of mature osteoclasts. Treatment with a specific Akt inhibitor disrupted sealing zone formation and decreased the bone-resorbing activity of osteoclasts. The normal microtubule structures were lost and the Akt inhibitor reduced the amount of acetylated tubulin, which reflects stabilized microtubules, whereas forced Akt activation by adenovirus vectors resulted in the opposite effect. Forced Akt activation increased the binding of the microtubule-associated protein adenomatous polyposis coli (APC), the APC-binding protein end-binding protein 1 (EB1) and dynactin, a dynein activator complex, with microtubules. Depletion of Akt1 and Akt2 resulted in a disconnection of APC/EB1 and a decrease in bone-resorbing activity along with reduced sealing zone formation, both of which were recovered upon the addition of LiCl, a glycogen synthase kinase-3β (GSK-3β) inhibitor. The Akt1 and Akt2 double-knockout mice exhibited osteosclerosis due to reduced bone resorption. These findings indicate that Akt controls the bone-resorbing activity of osteoclasts by stabilizing microtubules via a regulation of the binding of microtubule associated proteins.

Total ankle arthroplasty is a useful surgical procedure for osteoarthritis of the ankle, but aseptic loosening of components is an issue. We report here a case of aseptic implant loosening with metallosis after total ankle arthroplasty using the TNK ankle (Kyocera, Kyoto, Japan), which occurred despite the components being ceramic. We also report favorable results from our method of treatment using a total talar prosthesis in the revision surgery. During the revision surgery, synovial metallosis was found, probably related to superficial damage to the screw affixing the tibial component to the bone. Because both the tibial and talar components were loose, all the components and the remaining talar bone were removed. A new tibial component and a custom-made alumina-ceramic total talar prosthesis was inserted. Pain relief was achieved and maintained through the latest follow-up visit at 42 months after revision surgery. Dorsiflexion of the ankle improved from 0° to 5° and plantarflexion remained unchanged from its preoperative range of 20°. The American Orthopaedic Foot & Ankle Society ankle-hindfoot score improved from 38 to 80 points. To the best of our knowledge, this is the first reported case of an alumina-ceramic total ankle prosthesis loosening caused by metallosis resulting from screw abrasion. Favorable treatment results were obtained by using a total talar prosthesis in the revision surgery.

Patellar fracture is one of the most challenging complications of total knee arthroplasty, but relatively, little is known about it in patients with rheumatoid arthritis. We retrospectively analyzed 329 total knee arthroplasties performed in 230 female patients with rheumatoid arthritis to identify the incidence and risk factors for postoperative patellar fractures. The mean age was 61.8 years, and the mean follow-up period was 6.2 years. Patellar resurfacing was performed in all cases. Five postoperative patellar fractures (1.51%) were identified, and a thin residual patellar thickness and the use of posterior-stabilizing components were identified as significant risk factors, although the number of fractures was small in both groups. There was also tendency of higher age and greater joint line change observed in patients with fracture compared with those without fracture.

Bone homeostasis is maintained as a delicate balance between bone-resorption and bone-formation, which are coupled to maintain appropriate bone mass. A critical question is how bone-resorption is terminated to allow bone-formation to occur. Here, we show that TGFβs inhibit osteoclastogenesis and maintain bone-mass through Smad4 activity in osteoclasts. We found that latent-TGFβ1 was activated by osteoclasts to inhibit osteoclastogenesis. Osteoclast-specific Smad4 conditional knockout mice (Smad4-cKO) exhibited significantly reduced bone-mass and elevated osteoclast formation relative to controls. TGFβ1-activation induced expression of Irf8 and Bcl6, both of which encode factors inhibiting osteoclastogenesis, by blocking their negative regulator, Prdm1, in osteoclasts in a Smad4-dependent manner. Reduced bone-mass and accelerated osteoclastogenesis seen in Smad4-cKO were abrogated by Prdm1 deletion. Administration of latent-TGFβ1-Fc to wild-type mice antagonized LPS-induced bone destruction in a model of activated osteoclast-mediated bone destruction. Thus, latent-TGFβ1-Fc could serve as a promising new therapeutic agent in bone diseases marked by excessive resorption.

Osteoclasts are primary cells for bone resorption, and their differentiation is tightly regulated by receptor activator of nuclear factor kappa B ligand (RANKL) and a transcription factor nuclear factor-activated T cells (NFAT) c1. Recent studies have uncovered that the epigenetic regulation such as DNA methylation, histone methylation and acetylation, and micro RNAs play a critical role in cell differentiation. In particular, the expression of key developmental genes tends to be tightly regulated by trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3). Several reports have been proposed regarding the epigenetic regulation of osteoclast differentiation including this specific histone modification change. RANKL-induced NFATc1 expression is associated with the demethylation of H3K27me3 in osteoclast precursors. Jumonji domain containing-3 (Jmjd3), a H3K27 demethylase, is induced in murine bone marrow-derived macrophages in response to RANKL stimulation, and supposedly plays a critical role in the demethylation of H3K27me3 in the Nfatc1 gene and osteoclast differentiation.

Recent studies have uncovered that epigenetic regulation, such as histone methylation and acetylation, plays a critical role in determining cell fate. In particular, the expression of key developmental genes tends to be regulated by trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3). Osteoclasts are primary cells for bone resorption, and their differentiation is tightly regulated by the receptor activator of nuclear factor κB ligand (RANKL) and a transcription factor nuclear factor-activated T cell (NFAT) c1. We found that RANKL-induced NFATc1 expression is associated with the demethylation of H3K27me3. Jumonji domain containing-3, a H3K27 demethylase, is induced in bone marrow-derived macrophages in response to RANKL stimulation and may play a critical role in the demethylation of H3K27me3 in the Nfatc1 gene.

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.

The antiapoptotic molecule Bcl-2 inhibits apoptosis by preventing cytochrome c release from mitochondria. Although several studies have indicated the importance of Bcl-2 in maintaining skeletal integrity, the detailed cellular and molecular mechanisms remain elusive. Since Bcl-2 ―/― mice die before six weeks of age on account of renal failure and cannot be compared to adult wild-type mice, we generated Bcl-2 ―/― Bim +/― mice, in which a single Bim allele was inactivated, and compared them with their Bcl-2 +/― Bim +/― littermates. Bcl-2 ―/― Bim +/― mice grew normally, but exhibited decreased bone mass compared to Bcl-2 +/― Bim +/― mice, mainly due to impaired osteoblast function. Interestingly, the anabolic effect of parathyroid hormone (PTH) was not observed in Bcl-2 ―/― Bim +/― mice. This data demonstrates that Bcl-2 is indispensable for the anabolic activity of PTH in bone.

The anti-apoptotic molecule Bcl-2 inhibits apoptosis by preventing cytochrome c release from mitochondria. Although several studies have indicated the importance of Bcl-2 in maintaining skeletal integrity, the detailed cellular and molecular mechanisms remain elusive. Bcl-2(-/-) mice are growth-retarded and exhibit increased bone volume of the primary spongiosa, mainly due to the decreased number and dysfunction of osteoclasts. Osteoblast function is also impaired in Bcl-2(-/-) mice. Ex vivo studies on osteoblasts and osteoclasts showed that Bcl-2 promoted the differentiation, activation, and survival of both cell types. Because Bcl-2(-/-) mice die before 6 weeks of age due to renal failure and cannot be compared with adult wild type mice, we generated Bcl-2(-/-)Bim(+/-) mice, in which a single Bim allele was inactivated, and compared them with their Bcl-2(+/-)Bim(+/-) littermates. Loss of a single Bim allele restored normal osteoclast function in Bcl-2(-/-) mice but did not restore the impaired function of osteoblasts, and the mice exhibited osteopenia. These data demonstrate that Bcl-2 promotes the differentiation, activity, and survival of both osteoblasts and osteoclasts. The balance between Bcl-2 and Bim regulates osteoclast apoptosis and function, whereas other pro-apoptotic members are important for osteoblasts.

When an adolescent athlete presents with pain in the foot and ankle region, the diagnosis of tarsal coalition should be considered. Tarsal coalition is a congenital anomaly characterised by bony, cartilaginous or fibrous union of the bones in the hindfoot and midfoot. Most such coalitions are talocalcaneal or calcaneonavicular. Pain, peroneal spasm, rigid flatfoot, and a bony prominence inferior to the medial malleolus are typical signs and symptoms of such a coalition. The diagnosis can usually be made by plain X-ray. MRI, CT, and SPECT-CT are additional useful diagnostic modalities. In talocalcaneal coalition, the C sign and talar beaking are frequently visible in a lateral radiograph. Oblique radiographs of the foot are useful for detecting calcaneonavicular coalition. If conservative treatment such as reduced activity and cast immobilization is ineffective, excision of the coalition should be considered.

TGF-ß is a multifunctional cytokine that is involved in cell proliferation, differentiation and function. We previously reported an essential role of the TGF-ß -Smad2/3 pathways in RANKL-induced osteoclastogenesis. Using chromatin immunoprecipitation followed by sequencing, we comprehensively identified Smad2/3 target genes in bone marrow macrophages. These genes were enriched in the gene population upregulated by TGF-ß and downregulated by RANKL. Recent studies have revealed that histone modifications, such as trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3), critically regulate key developmental steps. We identified Nedd9 as a Smad2/3 target gene whose histone modification pattern was converted from H3K4me3(+)/H3K4me27(+) to H3K4me3(+)/H3K4me27(-) by TGF-ß. Nedd9 expression was increased by TGF-ß and suppressed by RANKL. Overexpression of Nedd9 partially rescued an inhibitory effect of a TGF-ß inhibitor, while gene silencing of Nedd9 suppressed RANKL-induced osteoclastogenesis. RANKL-induced osteoclastogenesis were reduced and stimulatory effects of TGF-ß on RANKL-induced osteoclastogenesis were partially abrogated in cells from Nedd9-deficient mice although knockout mice did not show abnormal skeletal phenotypes. These results suggest that Nedd9 is a Smad2/3 target gene implicated in RANKL-induced osteoclastogenesis.

Rheumatoid arthritis (RA) is an autoimmune destructive arthritis associated with CD4+ T cell-mediated immunity. Although expanded CD4+ T cell clones (ECs) has already been confirmed, the detailed characteristics of ECs have not been elucidated in RA. Using combination of a single-cell analysis and next-generation sequencing (NGS) in TCR repertoire analysis, we here revealed the detailed nature of ECs by examining peripheral blood (PB) from 5 RA patients and synovium from 1 RA patient. When we intensively investigated the single-cell transcriptome of the most expanded clones in memory CD4+ T cells (memory-mECs) in RA-PB, senescence-related transcripts were up-regulated, indicating circulating ECs were constantly stimulated. Tracking of the transcriptome shift within the same memory-mECs between PB and the synovium revealed the augmentations in senescence-related gene expression and the up-regulation of synovium-homing chemokine receptors in the synovium. Our in-depth characterization of ECs in RA successfully demonstrated the presence of the specific immunological selection pressure, which determines the phenotype of ECs. Moreover, transcriptome tracking added novel aspects to the underlying sequential immune processes. Our approach may provide new insights into the pathophysiology of RA.