Search

Objective We have previously reported that stimulation of mouse bone marrow-derived macrophages with tumor necrosis factor (TNF) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells. We undertook this study to clarify the characterization and function of human TNF and IL-6-induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. Methods Peripheral blood monocytes were cultured with a combination of TNF and IL-6, TNF alone, IL-6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL-6-induced osteoclasts or RANKL-induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole-body bone mineral density (BMD) was examined. Results Peripheral blood monocytes stimulated with a TNF and IL-6-induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL-6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL-6-induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL-6-induced osteoclasts, but not in RANKL-induced osteoclasts. The number of TNF and IL-6-induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL-induced osteoclast numbers negatively correlated with the whole-body BMD of the same patients. Conclusion Our results demonstrate that TNF and IL-6-induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.

Objectives: Current advancements in neuromuscular electrical stimulation (NMES) include belt-shaped electrode skeletal muscle electrical stimulation (B-SES), which was developed to induce whole leg muscle contraction in a single session. Delivering the optimal amount of stimulation is critical in NMES; therefore, we set out to establish a method to determine the B-SES stimulation intensity needed to induce muscle contraction sufficient for clinical purposes. Methods: We used the Auto Tens Pro system (Homer Ion Laboratory), which is a B-SES device. Stimulation at 20 Hz was delivered for 5 s, followed by 2 s rest. Twenty-four patients who were hospitalized for musculoskeletal diseases were enrolled at two hospitals. Patients were randomly assigned to one of three groups of subjectively graded stimulation intensities: moderate, strong, or very strong. To achieve each target intensity, we developed a structured verbal instruction protocol that aimed to help therapists deliver the target level of stimulation. As a physiological assessment of muscle contraction, serum lactate levels were measured before and after a single 20-min B-SES session. Results: The electric current intensity required to achieve a target subjective muscle contraction gradually increase according to the subjective contraction level. The increase in serum lactate level was significantly larger in the very strong group than in the moderate group. Conclusions: B-SES stimulators have the potential to induce efficient muscle strengthening in patients with musculoskeletal diseases. The structured verbal protocol developed here could help therapists achieve the appropriate stimulation intensity for each patient.

Oncologic emergency (OE) was observed in as many as 36% of patients with skeletal metastasis from unknown primary malignancy in this study. Delirium and respiratory failure were only two significant prognostic risk factors, which suggest that many of the OEs in untreated advanced cancer patients have probable chance to resolve. Early detection followed by appropriate treatment of such OEs is recommended., Aim Patients with skeletal metastasis from prediagnosed primary malignancy sometimes have concurrent oncologic emergency (OE) during the first visit. This study aims to investigate the types of OEs and treatment outcome in such patients. Methods We have experienced 359 patients with skeletal metastasis from unknown primary malignancy. Among them, 130 patients required immediate admission for OE treatment (OE group), 229 patients had no OE and did not required immediate admission (non‐OE group). Results The recognized types of OE were spinal cord compression in 60 patients, cancer pain in 30, hypercalcemia in 19, delirium in 16, deep vein thrombosis in 13, acute renal failure in 6, respiratory failure in 3, gastrointestinal hemorrhage in 3, and disseminated intravascular coagulation in 1. The overall 5‐year survival rates were 28% and 37% in the OE and non‐OE groups, respectively (P

X-ray Talbot-Lau interferometry is one of the x-ray phase imaging methods that has high sensitivity in depicting soft tissues. Unlike earlier x-ray phase imaging methods that required particular types of x-ray sources, such as a synchrotron or a micro-focus x-ray tube, x-ray Talbot-Lau interferometry enables to perform clinical x-ray phase imaging using a conventional x-ray source with a relatively compact configuration. We developed an apparatus to depict cartilage in the metacarpophalangeal joints of the hands. In addition, we examined the apparatus performance by applying it to healthy volunteers and patients with rheumatoid arthritis (RA). Cartilage deformation, which is thought to be a precursor of destruction of the joints, was successfully depicted by the apparatus, suggesting a potential early diagnosis of RA.

Background Loss of physical function is a clinical feature of RA. Total management including reconstructive joint surgery and rehabilitation should be needed for further improvements of physical function for established RA patients. In these days, it is very important to evaluate the effectiveness of joint surgery as well as drug therapy based on patient-reported outcome (PRO). Objectives The purpose of this study is to explore the relationship among depression, clinical variables and other PROs including physical function and improving of depressive status with joint surgery. Methods Multicenter prospective observational cohort study was conducted among patients who underwent elective joint surgery for RA from April 2012 to March 2016 (Study registration: UMIN000012649) (ref.1). In this study, we collected data at baseline and at 6 or 12 months after the surgery. These data were as follow; age, sex, disease duration, drug therapies, and disease activity (DAS28-CRP), and PRO measures [HAQ-DI, EQ-5D (QOL), pain VAS and BDI-II (depression)]. Correlation between BDI-II and other variables were determined using multiple liner regression analysis with forward stepwise. Results Totally, 346 patients before elective joint surgery were analyzed cross-sectionally. Mean age, disease duration, pain(VAS), DAS28, HAQ-DI, EQ-5D and BDI-II were 64.2 years, 17.0 years, 36.2 mm, 3.02, 1.111, 0.641 and 13.0, respectively. 52.6% of elective joint surgeries were in upper limbs and 47.4% were in lower limbs. Multiple liner regression analysis showed that HAQ-DI [β:-0.48, p Conclusion Loss of physical function is an important factor for impairment of depressive status as well as QOL in established RA patients. Improving of physical function with joint surgery in lower limbs caused improving of depressive status. Rheumatologists should take the joint surgery into consideration as effective intervention for treatment of established RA patients. References [1] Kojima T, et al. Int J Rheum Dis. 2018. doi: 10.1111/1756-185X.13394. Acknowledgement The registry used in this study was supported by a grant from the Ministry of Health, Labour and Welfare (H2424YN002-00) to Naoki Ishiguro Disclosure of Interests Toshihisa Kojima Grant/research support from: Chugai Pharmaceutical (Investigator Initiated Study), Novartis, Nippon Kayaku, Eli Lilly, Eisai, Speakers bureau: Chugai Pharmaceutical, Takeda Pharmaceutical, Pfizer, Eli Lilly Japan, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Astelas, UCB, Janssen Pharmaceutical, Tanabe Mitsubishi, Masayo Kojima: None declared, Hajime Ishikawa: None declared, Sakae Tanaka Grant/research support from: KYOCERA Corporation and Asahi Kasei Corporation, Consultant for: Amgen Astellas BioPharma K.K., KYOCERA Corporation, Pfizer and Daiichi Sankyo Co., Ltd., Speakers bureau: Asahi Kasei Corporation, Astellas Pharma Inc, Ayumi Pharmaceutical Corporation, Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe pharma Corporation, Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eli Lilly, Hisamitsu Pharmaceutical Co, Inc., Pfizer, Bristol-Myers., Keiichiro Nishida: None declared, Nobuhiko Haga: None declared, Yukio Masaoka: None declared, Jun Hashimoto: None declared, Hisaaki Miyahara: None declared, Yasuo Niki: None declared, Tomoatsu Kimura: None declared, Hiromi Oda: None declared, Shuji Asai Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Janssen, Takeda, and UCB Japan, Koji Funahashi: None declared, Naoki Ishiguro Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi-Sankyo, Eisai, Kaken, Mitsubishi Tanabe, Otsuka, Pfizer, Takeda, and Zimmer Biomet, Consultant for: Ono, Speakers bureau: Astellas, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, and Taisho Toyama

Background It is unclear whether antecedent primary malignancies (APMs) have any negative impact on the prognosis of soft tissue sarcoma (STS). We retrospectively reviewed STS patients with APMs (STS-APM) and compared their survival to those of STS only (STS-O). Methods Twenty-one cases of STS-APM from 2008 to 2017 in our institution were analyzed. One hundred and seventy cases of STS-O at the same period were compared as a control group. Overall survival was estimated using Kaplan-Meier survival curves and prognostic factors were analyzed using logistic regression analyses and contingency table analyses. Results As the final status of STS-APM patients, 12 patients were in disease-free survival, 5 were alive with disease, 3 have died of disease, and 1 has died of another disease. There was no case that died of APM. The 5-year overall survival rates were 88% in STS-APM and 78% in STS-O, showing no statistical significant ( p = 0.65). The 5-year overall survival rates in each stage of STS-APM and STS-O were 100/100% in stage I, 100/85% in stage II, 86/72% in stage III, and the 3-year overall survival rates were 67/51% in stage IV, with no statistical significance. With regard to prognostic factor, histological grade of STS was the only significant factor. Although antecedent radiotherapy tended to show a high odds ratio, the association was not statistically significant. Antecedent chemotherapy did not show any estimated prognostic risk. Conclusions Our study suggested that APM in STS patient would not be a negative prognostic factor.

To reduce the production of wear particles and subsequent aseptic loosening, we created a human articular cartilage-mimicked surface for a highly cross-linked polyethylene liner, whose surface grafted layer consisted of a biocompatible phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine). Although our previous in vitro findings showed that poly(2-methacryloyloxyethyl phosphorylcholine)-grafted particles were biologically inert and caused no subsequent bone resorptive responses, and poly(2-methacryloyloxyethyl phosphorylcholine) grafting markedly decreased wear in hip joint simulator tests, the clinical safety, and in vivo wear resistance of poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners remained open to question. Therefore, in the present study, we evaluated clinical and radiographic outcomes of poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners 5 years subsequent to total hip replacement in 68 consecutive patients. No reoperation was required for any reason, and no adverse events were associated with the implanted liners. The average Harris Hip Score increased from 38.6 preoperatively to 96.5 5 years postoperatively, and health-related quality of life, as indicated by the Short Form 36 Health Survey, improved. Radiographic analyses showed no periprosthetic osteolysis or implant migration. Between 1 and 5 years postoperatively, the mean steady-state wear rate was 0.002 mm/year, which represented a marked reduction relative to other highly cross-linked polyethylene liners, and appeared to be unaffected by patient-related or surgical factors. Although longer follow up is required, poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners improved mid-term clinical outcomes. The clinical safety and wear-resistance results are encouraging with respect to the improvement of long-term clinical outcomes with poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2007–2016, 2017.

Background Previously, we reported that novel osteoclast-like cells (OLCs) were induced, both in vitro and in vivo, from mouse bone marrow-derived macrophages (BMMs) by addition of a combination of TNFα and IL-61. Recently, O’Brien et al showed that TNF/IL-6 can drive osteoclastogenesis in BMMs from RANK-deficient mice2. Objectives We aimed to examine the differentiation of OLCs, which were induced by a combination of TNFα and IL-6 from human peripheral blood mononuclear cells (PBMCs) and CD14 +monocytes and to identify differences in molecular expression patterns between OLCs and conventional osteoclasts. Furthermore, we identified OLCs and osteoclasts on the bone tissue of the joint in patients with rheumatoid arthritis (RA). Methods PBMCs and CD14 +monocytes from healthy volunteers and/or RA patients were stimulated with TNFα and IL-6 or RANKL. Quantitative RT-PCR was used to measure mRNA expression levels of RANK, cathepsin K, calcitonin receptor, and dendritic cell-specific transmembrane protein. Prepared undecalcified tibial bone from 6 RA or osteoarthritis (OA) patients undergoing joint surgery were stained by tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry with anti-RANK antibody, expression of which were analysed. Osteoclasts and OLCs were identified as multinucleated TRAP+/RANK +cells and TRAP+/RANK- cells, respectively, adherent to the bone surface. Results The number of OLCs treated with a combination of TNFα and IL-6 from PBMCs or CD14 +monocytes in RA patients was significantly increased compared to that in healthy volunteers. Expression levels of RANK mRNA was clearly up-regulated in osteoclasts, and was obviously down-regulated in OLCs compared to that in osteoclast precursors. In cancellous bone, the number of TRAP+/RANK +osteoclasts was significantly increased in RA patients compared to that in OA patients. Interestingly, numerous TRAP+/RANK- OLCs were present in the cancellous bone of RA patients, while almost none were observed in the cancellous bone of OA patients. Conclusions The combination of TNFα and IL-6 strongly induced the differentiation of OLCs from PBMCs or CD14 +monocytes in RA patients. OLCs was characterised with TRAP+/RANK- multinucleated cells, which can distinguish conventional TRAP+/RANK +multinucleated osteoclasts. TRAP+/RANK- OLCs also were present in the bone tissue of RA patients. These results suggest that conventional osteoclasts and novel OLCs could be involved in the pathogenic mechanisms of inflammatory bone destruction such as RA. References [1] Yokota K, Sato K, Miyazaki T, Kitaura H, Kayama H, Miyoshi F, Araki Y, Akiyama Y, Takeda K, Mimura T. Combination of tumor necrosis factor α and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo. Arthritis Rheumatol 2014Jan;66(1):121–9. [2] O’Brien W, Fissel BM, Maeda Y, Yan J, Ge X, Gravallese EM, Aliprantis AO, Charles JF. RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis. Arthritis Rheumatol.2016Dec;68(12):2889–2900. Disclosure of Interest None declared

Background Total management including reconstructive joint surgery and rehabilitation should be needed for further improvements of physical function for long-standing RA patients. It is very important to set treatment goal for those management. Objectives The purpose of this study is to set treatment target using Timed Up and Go test (TUG) in relation to achievement of HAQ-DI remission (HAQ-DI Methods Multicenter prospective observational cohort study was conducted among patients who underwent elective joint surgery for RA from April 2012 to March 2016 (Study registration: UMIN000012649). In this study, we collected data including age, sex, disease duration, drug therapies, and disease activity (DAS), TUG, and patient-reported outcome [HAQ-DI, EQ-5D (QOL), patient’s global assessment (PtGA) and BDI-II (depression)] at baseline and at 6 or 12 months after the surgery. Association between TUG and achievement of HAQ remission and cut-off values for HAQ remission were also determined using logistic regression analysis with adjustment of age and sex and ROC curve, respectively. Results Totally, 139 patients with elective joint surgery in lower limbs were analysed. Mean age, disease duration, HAQ-DI and TUG were 65.4 years, 17.5 years, 1.022, and 12.7 s, respectively. Performed joint surgeries were total hip arthroplasty; 10.1%, total knee arthroplasty; 33.8%, total ankle arthroplasty or ankle fixation; 10.1%, and forefoot arthroplasty; 46.0%. The surgeries can significantly improve the outcome measures, including TUG, DAS, PtGA, pain, EQ-5D and BDI-II other than HAQ-DI. In this study, 45 of 139 patients (32.4%) had HAQ remission status at baseline. 18 of 94 patients (19.1%) who had HAQ-DI >0.5 can achieve HAQ remission with the surgery. Notably, TUG at last observation was significantly associated with achievement of HAQ remission even after adjustment for age, sex, and DAS (1 s increasing of TUG. OR:0.72, 95% CI: 0.53–0.97). The adjusted-TUG at last observation of patients with achievement of HAQ remission was 9.2 s (95% CI: 5.6–12.8) (figure 1). Cut-off of TUG at observation for achievement of HAQ remission was 9.2 s based on ROC analysis (figure 2). Importantly, We confirmed significant more improving of EQ-5D, HAQ-DI and TUG in patients who achieved TUG 9.2 s at last observation than in patients who did not (figure 3). Conclusions TUG was significantly associated with PRO; HAQ-DI and EQ-5D. The cut-off values of TUG (9.2 s) should be important to achieve good QOL and physical function for patients with joint surgery in lower limbs and could be suitable target for surgical procedure. Acknowledgements This study is supported by grant from the Japanese Ministry of Health, Labour and Welfare Disclosure of Interest None declared

Daily and weekly administration of teriparatide (PTH1–34) reduces the risk of osteoporotic bone fractures. However, their effects on markers of bone formation and bone resorption differ. These results indicate that the dosing frequency of teriparatide may affect bone metabolism and bone structure, with different effects on bone strength. In the present study, to evaluate the dose-related effects of a low administration frequency of teriparatide on bone status, we investigated the effects of three-times-weekly administration of teriparatide (1.1, 5.6, or 28.2 µg/kg) for 12 months on bone parameters, including bone metabolism markers, bone mineral density (BMD), micro-computed tomography, and bone strength, using 6-month-old ovariectomized (OVX) rats. Three-times-weekly administration of teriparatide dose-dependently increased the BMD of the lumbar vertebra and femur in OVX rats, and increased serum osteocalcin (a marker of bone formation), but not type I collagen C-telopeptide (a marker of bone resorption). The trabecular number and thickness increased in the vertebrae and femur, as in prior reports of daily teriparatide administration in OVX rats. Cortical thickness increased only toward the endocortical side of the femur, unlike with daily administration. Bone strength of the vertebrae and proximal and shaft of the femur was correlated with the changes in BMD and bone structure. These results demonstrate the effects of low frequency, intermittent administration of teriparatide on the biomechanical, and microstructural properties of bone in OVX rats. Electronic supplementary material The online version of this article (doi:10.1007/s00223-015-9998-0) contains supplementary material, which is available to authorized users.

Objective: To explore the characteristics of functional impairment in patients with established rheumatoid arthritis (RA) based on the range of motion (ROM) of joints in a prospective observational study of RA patients undergoing joint surgery. Methods: We collected data on demographics, Health Assessment Questionnaire Disability Index (HAQ-DI), and the ROM of large joints including the shoulder, elbow, wrist, hip, knee, and ankle. Associations between the ROM of each joint and disability in the eight HAQ-DI categories were determined using receiver operating characteristic (ROC) and logistic regression analyses. ROM cut-off values of each joint for the absence of disability in each HAQ-DI category were determined using ROC curves. Results: A total of 460 patients were enrolled and analyzed in this study. Based on ROC analysis, the ROM of each joint was significantly associated with disability in each category. After adjusting for disease activity, age, and sex, shoulder abduction had the highest independent impact on disability in activity [cut-off: 139 degrees (OR: 5.26)], elbow flexion-extension in dressing [121 degrees (OR: 2.22)], wrist flexion-extension in reach [86 degrees (OR: 2.71)], hip flexion-extension in walking [126 degrees (OR: 3.42)], and knee flexion-extension in walking [134 degrees (OR: 2.97)]. Conclusions: Limited ROM of multiple joints was significantly associated with functional impairment in patients with long-standing RA. Motion in daily activity involves multiple joints, and at least two joints were independently involved in disability., Published online: 25 Jul 2017

Complete circumferential osseous extension in the acetabular rim has been reported to occur in the deep hip with pincer impingement. However, this phenomenon occasionally is observed in dysplastic hips without pincer impingement, and the degree to which this finding might or might not be associated with hip pain, and how often it occurs bilaterally among patients, are not well characterized. (1) To determine the proportion of patients with complete circumferential osseous extension in the acetabular rim using three-dimensional (3-D) CT in patients with and without hip pain who had CT scans obtained for various reasons. (2) To elucidate how often this complete circumferential osseous extension occurred bilaterally among those patients. (3) To investigate the relationship between the proportions of patients with complete circumferential osseous extension observed on CT scans among three different acetabular coverage groups: dysplasia, normal, and overcoverage. (4) To determine how often the finding of hip pain was associated with complete circumferential osseous extension. Between September 2011 to July 2016, we evaluated 3788 patients with pelvic complaints such as hip, groin, thigh, buttock, or sacroiliac joint pain. We obtained consent from 26% (992 of 3788) of them, and obtained 3-D CT scans as part of that evaluation. For the current retrospective study, we excluded patients younger than 20 years or 80 years or older (181 patients), patients who had previous hip surgery (185 patients), patients with severe osteoarthritis with Tonnis Grades 2 or 3 (301 patients), and patients who could not have an accurate lateral center-edge (LCE) angle measured owing to poor-quality radiographs (24 patients), leaving 301 patients (602 hips) for this analysis. In this study population, patients reported pain in 131 hips (22%), defined as all types of hip pain except for trauma, including activity pain, pain with sports, pain on motion, and impingement pain; the others did not report hip pain. The mean age of the patients was 56 ± 16 years, and the mean LCE angle was 26° ± 8° (range, −9° to 47°). We first determined the proportion of patients with complete circumferential osseous extension in the acetabular rim using 3-D CT for those with and without hip pain who had CT obtained for various reasons. We next elucidated how often this complete circumferential osseous extension occurred bilaterally among the patients, and finally we investigated the relationship between the proportion of patients with complete circumferential osseous extension observed on CT scans among the three groups: dysplasia (defined as LCE angles of 22° or smaller), normal, and overcoverage (defined as LCE angles of 34° or larger) groups. We finally determined how often the finding was associated with hip pain attributable to complete circumferential osseous extension. The proportion of patients with complete circumferential osseous extension was 6% (18 of 301 patients). Eighty-nine percent (16 of 18) of the patients had bilateral complete circumferential osseous extension. There were no differences in the proportions of patients with complete circumferential osseous extension among the three groups: 5.3% (odds ratio [OR], 1.02; 95% CI, 0.45-2.31; p = 0.97), 5.3%, and 7.4% (OR, 0.70; 95% CI, 0.28-1.73; p = 0.44) in the dysplasia, normal, and overcoverage groups, respectively, with the numbers available. Eighteen percent (six of 34) of the hips with complete circumferential osseous extension had pain. Complete circumferential osseous extension in the acetabular rim is relatively uncommon. When it occurs, it usually is bilateral, it occurs regardless of acetabular coverage, and it is associated with pain in a minority of patients. Level III, prognostic study.

Objective. To clarify the obstacles preventing the implementation of the treat-to-target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice. Methods. A total of 301 rheumatologists in Japan completed a questionnaire. In the first section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application. Results. Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations. Conclusion. Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain.

A virtual screening method achieved a maximum boost in speed of several tens of thousands–fold while determining the interface structure., Interfaces markedly affect the properties of materials because of differences in their atomic configurations. Determining the atomic structure of the interface is therefore one of the most significant tasks in materials research. However, determining the interface structure usually requires extensive computation. If the interface structure could be efficiently predicted, our understanding of the mechanisms that give rise to the interface properties would be significantly facilitated, and this would pave the way for the design of material interfaces. Using a virtual screening method based on machine learning, we demonstrate a powerful technique to determine interface energies and structures. On the basis of the results obtained by a nonlinear regression using training data from 4 interfaces, structures and energies for 13 other interfaces were predicted. Our method achieved an efficiency that is more than several hundred to several tens of thousand times higher than that of the previously reported methods. Because the present method uses geometrical factors, such as bond length and atomic density, as descriptors for the regression analysis, the method presented here is robust and general and is expected to be beneficial to understanding the nature of any interface.

Aberrant histone lysine methylation (HKM) has been reported in rheumatoid arthritis (RA) synovial fibroblasts (SFs). As histone lysine methyltransferases (HKMTs) and demethylases (HKDMs) regulate HKM, these enzymes are believed to be dysregulated in RASFs. The aim of this study is to clarify whether gene expressions of HKMTs and HKDMs are altered in RASFs.SFs were isolated from synovial tissues obtained from RA or osteoarthritis (OA) patients during total knee joint replacement. The mRNA levels of 34 HKMTs and 22 HKDMs were examined after stimulation with tumour necrosis factor α (TNF-α) in RASFs and OASFs.The gene expression of the 12 HKMTs, including MLL1, MLL3, SUV39H1, SUV39H2, PRDM2, EZH2, SETD2, NSD2, NSD3, SMYD4, DOT1, and PR-set7, that catalyse the methylation of H3K4, H3K9, H3K27, H3K36, H3K79, or H4K20 was higher after TNFα stimulation in RASFs vs. OASFs. The gene expression of the 4 HKDMs, including FBXL10, NO66, JMJD2D, and FBXL11, that catalyse the methylation of H3K4, H3K9, or H3K36 was higher after TNFα stimulation in RASFs vs. OASFs.The study findings suggest that the HKM-modifying enzymes are involved in the alteration of HKM, which results in changes in the gene expression of RASFs.

Steffel et al. [(1)][1] found that elderly atrial fibrillation patients receiving anticoagulation therapy and at increased fall risk had increased rate of bone fractures due to falling, which was similar between the use of 2 anticoagulants, edoxaban and warfarin (adjusted hazard ratio: 0.94; 95%

Since biologic agents were introduced to treat rheumatoid arthritis (RA) in 2003, the number of orthopedic surgical procedures under treatment with biologic agents has been increasing in Japan. However, whether biologic agents cause an increase in the prevalence of postoperative complications is as yet unknown. The Committee on Arthritis of the Japanese Orthopedic Association investigated the prevalence of postoperative complications in patients with RA in teaching hospitals in Japan.Between January 2004 and November 2008, surveillance forms about medications and surgical procedures in patients with RA were sent to 2,019 teaching hospitals. Data were analyzed by the Rheumatoid Arthritis Committee.Biologic agents were administered to RA patients in 632 of 1,245 hospitals (50.8%); 430 of the 1,245 hospitals (34.5%) used surgical intervention under treatment with biologic agents. The number of surgical procedures under treatment with biologic agents was 3,468, and the prevalence of infection was 1.3% (46 cases). The prevalence of infection was 1.0% (567 procedures) in 56,339 procedures under treatment with nonbiologic disease-modifying anti-rheumatic drugs. There were no significant differences between biological and nonbiological treatment groups with respect to the prevalence of infection. In the joint arthroplasty group, the number of procedures under biological and nonbiological treatment was 1,626 and 29,903, and the prevalence of infection was 2.1% (34 procedures) and 1.0% (298 procedures), respectively. There was a significant difference between groups. The odds ratio was 2.12 (95% confidence interval 1.48-3.03, P0.0001).The chance of having biological treatment with joint arthroplasty was more than twofold greater in patients with surgical-site infections compared with those treated with nonbiologic agents. Caution is required for surgical procedure, perioperative course, and obtaining consent for joint arthroplasty for patients with RA undergoing surgery under biological agents.

Objective Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs. Methods MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 (WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6. Results The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs. Conclusion Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6–induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs.

In addition to other chronic diseases such as hypertension, hypercholesterolemia, and diabetes, a treat-to-target strategy was recently applied in rheumatoid arthritis and has now been discussed in osteoporosis. An important goal of osteoporosis therapy is normal risk of hip fracture associated with significant morbidity and mortality, but the anti-fracture efficacies of currently approved drugs are limited (1, 2). Although fundamental methods to effectively prevent osteoporotic fracture include pharmacological treatment of sarcopenia that results in improving bone fragility as well as reducing fall risk, the present article focuses on anti-sclerostin antibodies such as romosozumab and blosozumab, the investigational agents for osteoporosis, and provides new insights into their effects from natural homeostatic system in the skeleton.

SKELETAL ADAPTATION TO MECHANICAL STRAIN IN HUMANS Several lines of clinical evidence (1–3) suggest that the adult skeleton in humans continuously responds to change in mechanical environment to maintain resultant “elastic” deformation (strain) of bone; increased or decreased bone strain would normally induce bone gain or loss, respectively. Indeed, skeletal adaptation to mechanical strain, known as the mechanostat (4–6), plays a significant role in the treatment of osteoporosis. For example, bone strain from habitual physical activity decreases when an osteoporosis drug increases bone strength, indicating that the effect of osteoporosis therapy is limited by mechanical strain-related feedback control; this mechanostat-based logic is consistent with various clinical data (3). Approaches to reduce the limitation of osteoporosis therapy include pharmacologically enhancing skeletal response to mechanical loading, and earlier experimental studies using external mechanical loading models show that intermittent treatment with parathyroid hormone has such a possibility (7, 8). Importantly, treatment with teriparatide could synergistically produce bone gain with even low, physiological levels of mechanical loading in humans (9) as well as animals (10). The present article concisely discusses the effects of daily or weekly treatment with teriparatide and proposes a new mechanostat-based hypothesis for bone quality associated with mineral versus collagen. DAILY OR WEEKLY TREATMENT WITH TERIPARATIDE IN OSTEOPOROSIS In Japan, not only daily subcutaneous injection of teriparatide (20 μg/day) (11– 13) but also weekly subcutaneous injection of teriparatide (56.5 μg/week) (14, 15) has been approved for the treatment of adult osteoporosis patients with high risk of fracture. Interestingly, there are marked differences in the effects of these two treatments on circulating markers of bone formation and resorption. The daily injection results in a rapid and sustained increase in bone formation markers followed by a delayed increase in bone resorption markers (12); the period of time during which the increase in bone formation is superior to that in bone resorption is called the anabolic window (16). In contrast, the weekly injection induces only a transient increase in bone formation markers without an increase in bone resorption markers (14). Formation and resorption occur on different surfaces during bone modeling, and thus modeling-based bone formation and resorption are not coupled; such uncoupling factors include mechanical loading that stimulates bone formation and suppresses bone resorption. Modeling-based bone formation by histomorphometry (17, 18) as well as an increase in bone formation markers and a decrease in bone resorption markers in blood (19) are observed during the first month of daily treatment with teriparatide, which is consistent with clinical finding suggesting that daily treatment with teriparatide and normal physical activity synergistically produce bone gain (9). A rapid but transient increase in bone formation markers without an increase in bone resorption markers (14) implies that weekly treatment with teriparatide also stimulates modeling-based bone formation. On the other hand, long-term daily, but not weekly, treatment with teriparatide causes increases in both bone formation and resorption markers (12, 14). These systemic changes agree with histomorphometric data showing that 1 or 2 years of daily treatment with teriparatide results in an increase in remodeling-based bone formation (20); resorption followed by formation occurs on the same surface during bone remodeling and thus remodelingbased bone resorption and formation are coupled. Increased or decreased bone remodeling lowers or raises, respectively, the degree of mineralization (21), and cortical volumetric bone mineral density (BMD) is decreased after daily treatment with teriparatide (13). In contrast, weekly treatment with teriparatide is unlikely to increase bone remodeling because neither an increase in bone resorption markers nor a decrease in cortical volumetric BMD is not found (14, 15).

Background Several kinds of thermally processed hydroxyapatite have been commonly used for bone defects due to bone diseases or fractures instead of autologous bone grafts. However, these materials do not change in form during surgery and are not absorbed over a long period. To overcome this disadvantage, calcium phosphate bone cements (CPCs) have been developed and are already in use in clinical cases. These materials have merit in that to be formed in situ they are injectable and absorbable, but there are still problems with their handling and their hardening properties. A newly developed CPC called XSB-671D hardens earlier and is more resistant to body fluids than other CPCs. The purpose of this article is to verify the effectiveness, safety and usefulness of this CPC (XSB- 671D) as a bone defect filler. Methods We conducted clinical trials at five medical institutions based on a unified protocol in a total of 75 cases (30 males, 45 females). We observed the postoperative constitutional symptoms and local symptoms of the filling sites. The effectiveness of this material was evaluated by radiographs of the filled sites, and blood and urine were examined to evaluate any adverse effects. Results The ratio of the cases determined to be “effective” or “better” among the 74 cases we found qualified was 97.3%, and XSB-671D was confirmed to be a highly effective material with beneficial effects of biocompatibility and osteoconduction as a bone defect filler. Additionally, there were no adverse effects caused by XSB-671D except one local skin reaction, which disappeared 2 weeks later; its safety was also thus verified. Conclusions We conclude that effective, safe treatment is possible using XSB-671D in cases requiring filling of a bone defect as well as those with serious osteoporosis.

The receptor activator of NF-kappaB ligand (RANKL), a critical regulator of osteoclastogenesis, is synthesized as a membrane-anchored protein and cleaved into a soluble form by ectodomain shedding. We developed an assay system to identify molecules regulating the RANKL shedding. Using this system, we found that a splice variant of Ca2+-promoted Ras inactivator (CAPRI), deltaCAPRI, which is expressed in primary osteoblasts, promoted the RANKL shedding. The wild type CAPRI is a member of the Ras GTPase-activating protein (GAP) family and suppresses Ca2+-dependent Ras activation, whereas deltaCAPRI, which lacks one exon in the GAP-related domain, activated the Ras pathway. Overexpression of deltaCAPRI or a constitutive active form of Ras up-regulated the expression level of matrix-metalloproteinase 14 (MMP14), which directly cleaves the ectodomain of RANKL, whereas Erk activation by expressing the constitutive active Mek1 did not affect the MMP14 expression or RANKL shedding. These results suggest that deltaCAPRI is a possible regulator of RANKL shedding by modulating MMP14 expression through Ras signaling cascades other than the Erk pathway.

Schwann cells are the myelinating glia of the peripheral nervous system, and their development is regulated by various growth factors, such as neuregulin, platelet-derived growth factor (PDGF), and insulin-like growth factor-I (IGF-I). However, the mechanism of intracellular signaling pathways following these ligand stimuli in Schwann cell differentiation remains elusive. Here, we demonstrate that in cultured Schwann cells, neuregulin and PDGF suppressed the expression of myelin-associated protein markers, whereas IGF-I promoted it. Although these ligands activated common downstream signaling pathways [i.e., extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt pathways], the profiles of activation varied among ligands. To elucidate the function of these pathways and the mechanisms underlying Schwann cell differentiation, we used adenoviral vectors to selectively activate or inactivate these pathways. We found that the selective activation of Erk pathways suppressed Schwann cell differentiation, whereas that of PI3K pathways promoted it. Furthermore, lithium chloride, a modulator of glycogen synthase kinase-3β (GSK-3β) promoted Schwann cell differentiation, suggesting the involvement of GSK-3β as a downstream molecule of PI3K-Akt pathways. Selective activation of PI3K pathways in Schwann cells by gene transfer also demonstrated increased myelination inin vitroSchwann cell-DRG neuron cocultures andin vivoallogenic nerve graft experiments. We conclude that signals mediated by PI3K-Akt are crucial for initiation of myelination and that the effects of growth factors are primarily dependent on the balance between Erk and PI3K-Akt activation. Our results also propose the possibility of augmenting Schwann cell functions by modulating intracellular signals in light of future cell therapies.

Objective Chondromodulin I (ChM-I), a cartilage matrix protein, promotes the growth and proteoglycan synthesis of chondrocytes. However, it also inhibits angiogenesis. Since ChM-I is expressed not only in cartilage, but also in the thymus, we investigated the modulation of T cell function by ChM-I to assess its therapeutic potential in rheumatoid arthritis (RA). Methods The localization of ChM-I expression in mouse thymus tissue was examined by in situ hybridization. The proliferative response of peripheral blood T cells and synovial cells obtained from patients with RA was evaluated by 3H-thymidine incorporation assay. The effects of ChM-I were examined using recombinant human ChM-I (rHuChM-I). Modulation of the antigen-specific immune response was evaluated by the recall response of splenic T cells and the delayed-type hypersensitivity response induced in the ear of mice primed with ovalbumin (OVA). Antigen-induced arthritis (AIA) was induced in mice by injecting methylated bovine serum albumin into the ankle joints 2 weeks after the priming. Results ChM-I was expressed in the cortex of the thymus. Recombinant human ChM-I suppressed the proliferative response of mouse splenic T cells and human peripheral blood T cells stimulated with anti-CD3/CD28 antibodies, in a dose-dependent manner. Production of interleukin-2 was decreased in rHuChM-I–treated mouse CD4 T cells. Ten micrograms of rHuChM-I injected intraperitoneally into OVA-primed mice suppressed the induction of the antigen-specific immune response. Finally, rHuChM-I suppressed the development of AIA, and also suppressed the proliferation of synovial cells prepared from the joints of patients with RA. Conclusion These results suggest that ChM-I suppresses T cell responses and synovial cell proliferation, implying that this cartilage matrix protein has a therapeutic potential in RA.

Despite the early widespread clinical success with cemented stems using the second generation cement technique, many changes were introduced into stem design and material. In more recent years, many early failures of cemented stems have been reported. Many of these introduced changes based on industrial investigations, including circular stem cross-section, rough surface finish, increased stem offset, modular head-neck system, PMMA pre-coating and titanium alloy, have resulted in failure due to biological diversity and reactions. Failed stems were all designed as a composite-beam system with a rough surface finish. Composite-beam stems were less tolerant of human factors, compared to those incorporating the Taper-slip system with a smooth surface finish. Consequently, new design features should be introduced prudently with extensive pre-market testing, limited clinical release, and careful post-market surveillance. By reviewing the past history of total hip replacement, we learn an important lesson in view of the relationship between industrial innovation and clinical application. In this way we can take a lesson from the evolution of total hip replacement and understand “Yesterday's Successes and Today's Failures”.

Osteoclasts are cells of monocyte/macrophage origin that erode bone matrix: regulation of their differentiation is central to the understanding of the pathogenesis and treatment of bone diseases such as osteoporosis. Signalling by RANKL (receptor activator of NF-kappaB ligand), also known as Tnfsf11, is essential for the induction of osteoclast differentiation, and it must be strictly regulated to maintain bone homeostasis. But it is not known whether RANKL signalling to the cell interior is linked to any regulatory mechanisms. Here we show that RANKL induces the interferon-beta (IFN-beta) gene in osteoclast precursor cells, and that IFN-beta inhibits the differentiation by interfering with the RANKL-induced expression of c-Fos, an essential transcription factor for the formation of osteoclasts. This IFN-beta gene induction mechanism is distinct from that induced by virus, and is dependent on c-Fos itself. Thus an autoregulatory mechanism operates-the RANKL-induced c-Fos induces its own inhibitor. The importance of this regulatory mechanism for bone homeostasis is emphasized by the observation that mice deficient in IFN-beta signalling exhibit severe osteopenia (loss of bone mass) accompanied by enhanced osteoclastogenesis. Our study places the IFN-beta system in a new context, and may offer a molecular basis for the treatment of bone diseases.

Interfaces have atomic structures that are significantly different from those in the bulk, and play crucial roles in material properties. The central structures at the interfaces that provide properties have been extensively investigated. However, determination of even one interface structure requires searching for the stable configuration among many thousands of candidates. Here, a powerful combination of machine learning techniques based on kriging and transfer learning (TL) is proposed as a method for unveiling the interface structures. Using the kriging+TL method, thirty-three grain boundaries were systematically determined from 1,650,660 candidates in only 462 calculations, representing an increase in efficiency over conventional all-candidate calculation methods, by a factor of approximately 3,600.

Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs.MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 (WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6.The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs.Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6-induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs.

Bone is a highly vascularized organ, thus angiogenesis is a vital process during bone remodeling. However, the role of vascular systems in bone remodeling is not well recognized. Here we show that netrin-4 inhibits osteoclast differentiation in vitro and in vivo. Co-cultures of bone marrow macrophages with vascular endothelial cells markedly inhibited osteoclast differentiation. Adding a neutralizing antibody, or RNA interference against netrin-4, restored in vitro osteoclast differentiation. Administration of netrin-4 prevented bone loss in an osteoporosis mouse model by decreasing the osteoclast number. We propose that vascular endothelial cells interact with bone in suppressing bone through netrin-4.

Synovial fibroblasts, established in culture from patients with RA, were treated with proinflammatory cytokines and prostaglandin E(2) (PGE(2)) for 24 h. These cells enhanced the production and the messenger RNA expression of PTH-related peptide (PTHrP) using proinflammatory cytokines, such as interleukin (IL)-1alpha, tumor necrosis factor-alpha without the coordination of other cytokines. In addition, PGE(2) which has been induced with IL-1, also enhanced the production of PTHrP. The IL-1alpha-induced PTHrP production was inhibited by PG H synthetase (Cox) inhibitors, indomethacin, and also by Cox-2 inhibitor, NS398. The synovial fibroblasts expressed PGE(2) receptor subtypes, EP2, EP3, EP4, but not EP1, as detected by RT-PCR. Of the PGE(2) receptor agonists, EP4 agonist showed the most marked induction of PTHrP, and EP2 agonist partly induced the production. However, these PGE(2) receptors were not induced by the treatment with IL-1alpha and PGE(2). These results suggest that induction of PGE(2) by IL-1alpha may be an important component of the PTHrP production of the inflammatory process in synovial tissues from patients with RA. These findings are the first to demonstrate that PGE(2) stimulates PTHrP production, which is mediated mostly by EP2 and EP4 receptors.

Involuted intraosseous lipoma with extensive fat necrosis resulting in cyst formation (Milgram stage III) is distinguishable from lesions without necrosis (stage I) or lesions with focal fat necrosis (stage II), based on differences in signal intensity on magnetic resonance imaging (MRI). Fat tissue has a high signal intensity on both T1- and T2-weighted MR images, whereas the extensive fat necrosis that results in cyst formation shows high signal intensity on T2-weighted images and low intensity on T1-weighted images. We report a patient in whom an intraosseous lipoma with high signal intensity on both T1- and T2-weighted MRI was found to be extensively involuted on histopathologic examination. Intraosseous lipoma appears to undergo spontaneous involution. In some patients, therefore, surgical excision may not be necessary. A correct preoperative diagnosis should reduce the necessity for a biopsy or surgery. Although lesions classified as stage I or II are easily identified by MRI, those of stage III are difficult to diagnose preoperatively by this method.

Bone resorption is regulated by the immune system, where T-cell expression of RANKL (receptor activator of nuclear factor (NF)-kappaB ligand), a member of the tumour-necrosis factor family that is essential for osteoclastogenesis, may contribute to pathological conditions, such as autoimmune arthritis. However, whether activated T cells maintain bone homeostasis by counterbalancing the action of RANKL remains unknown. Here we show that T-cell production of interferon (IFN)-gamma strongly suppresses osteoclastogenesis by interfering with the RANKL-RANK signalling pathway. IFN-gamma induces rapid degradation of the RANK adapter protein, TRAF6 (tumour necrosis factor receptor-associated factor 6), which results in strong inhibition of the RANKL-induced activation of the transcription factor NF-kappaB and JNK. This inhibition of osteoclastogenesis is rescued by overexpressing TRAF6 in precursor cells, which indicates that TRAF6 is the target critical for the IFN-gamma action. Furthermore, we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFN-gamma-induced activation of the ubiquitin-proteasome system. Our study shows that there is cross-talk between the tumour necrosis factor and IFN families of cytokines, through which IFN-gamma provides a negative link between T-cell activation and bone resorption. Our results may offer a therapeutic approach to treat the inflammation-induced tissue breakdown.

To examine the role of mitogen-activated protein kinase and nuclear factor kappa B (NF-kappaB) pathways on osteoclast survival and activation, we constructed adenovirus vectors carrying various mutants of signaling molecules: dominant negative Ras (Ras(DN)), constitutively active MEK1 (MEK(CA)), dominant negative IkappaB kinase 2 (IKK(DN)), and constitutively active IKK2 (IKK(CA)). Inhibiting ERK activity by Ras(DN) overexpression rapidly induced the apoptosis of osteoclast-like cells (OCLs) formed in vitro, whereas ERK activation after the introduction of MEK(CA) remarkably lengthened their survival by preventing spontaneous apoptosis. Neither inhibition nor activation of ERK affected the bone-resorbing activity of OCLs. Inhibition of NF-kappaB pathway with IKK(DN) virus suppressed the pit-forming activity of OCLs and NF-kappaB activation by IKK(CA) expression upregulated it without affecting their survival. Interleukin 1alpha (IL-1alpha) strongly induced ERK activation as well as NF-kappaB activation. Ras(DN) virus partially inhibited ERK activation, and OCL survival promoted by IL-1alpha. Inhibiting NF-kappaB activation by IKK(DN) virus significantly suppressed the pit-forming activity enhanced by IL-1alpha. These results indicate that ERK and NF-kappaB regulate different aspects of osteoclast activation: ERK is responsible for osteoclast survival, whereas NF-kappaB regulates osteoclast activation for bone resorption.