Metallothionein 3 promotes osteoclast differentiation and survival by regulating the intracellular Zn2+ concentration and NRF2 pathway.

In osteoclastogenesis, the metabolism of metal ions plays an essential role in controlling reactive oxygen species (ROS) production, mitochondrial biogenesis, and survival, and differentiation. However, the mechanism regulating metal ions during osteoclast differentiation remains unclear. The metal-binding protein metallothionein (MT) detoxifies heavy metals, maintains metal ion homeostasis, especially zinc, and manages cellular redox levels. We carried out tests using murine osteoclast precursors to examine the function of MT in osteoclastogenesis and evaluated their potential as targets for future osteoporosis treatments. MT genes were significantly upregulated upon differentiation from osteoclast precursors to mature osteoclasts in response to receptor activators of nuclear factor-κB (NF-κB) ligand (RANKL) stimulation, and MT3 expression was particularly pronounced in mature osteoclasts among MT genes. The knockdown of MT3 in osteoclast precursors demonstrated a remarkable inhibition of differentiation into mature osteoclasts. In preosteoclasts, MT3 knockdown suppressed the activity of mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways upon RANKL stimulation, leading to affect cell survival through elevated cleaved Caspase 3 and poly (ADP-ribose) polymerase (PARP) levels. Additionally, ROS levels were decreased, and nuclear factor erythroid 2-related factor 2 (NRF2) (a suppressor of ROS) and the downstream antioxidant proteins, such as catalase (CAT) and heme oxygenase 1 (HO-1), were more highly expressed in the MT3 preosteoclast knockdowns. mitochondrial ROS, which is involved in mitochondrial biogenesis and the production of reactive oxygen species, were similarly decreased because cAMP response element-binding (CREB) and peroxisome proliferator-activated receptor γ coactivator 1ß (PGC-1ß) were less activated due to MT3 depletion. Thus, by modulating ROS through the NRF2 pathway, MT3 plays a crucial role in regulating osteoclast differentiation and survival, acting as a metabolic modulator of intracellular zinc ions.

Deep learning-based automatic-bone-destruction-evaluation system using contextual information from other joints.

BACKGROUND: X-ray images are commonly used to assess the bone destruction of rheumatoid arthritis. The purpose of this study is to propose an automatic-bone-destruction-evaluation system fully utilizing deep neural networks (DNN). This system detects all target joints of the modified Sharp/van der Heijde score (SHS) from a hand X-ray image. It then classifies every target joint as intact (SHS = 0) or non-intact (SHS ≥ 1). METHODS: We used 226 hand X-ray images of 40 rheumatoid arthritis patients. As for detection, we used a DNN model called DeepLabCut. As for classification, we built four classification models that classify the detected joint as intact or non-intact. The first model classifies each joint independently, whereas the second model does it while comparing the same contralateral joint. The third model compares the same joint group (e.g., the proximal interphalangeal joints) of one hand and the fourth model compares the same joint group of both hands. We evaluated DeepLabCut's detection performance and classification models' performances. The classification models' performances were compared to three orthopedic surgeons. RESULTS: Detection rates for all the target joints were 98.0% and 97.3% for erosion and joint space narrowing (JSN). Among the four classification models, the model that compares the same contralateral joint showed the best F-measure (0.70, 0.81) and area under the curve of the precision-recall curve (PR-AUC) (0.73, 0.85) regarding erosion and JSN. As for erosion, the F-measure and PR-AUC of this model were better than the best of the orthopedic surgeons. CONCLUSIONS: The proposed system was useful. All the target joints were detected with high accuracy. The classification model that compared the same contralateral joint showed better performance than the orthopedic surgeons regarding erosion.

Factors affecting patient satisfaction related to cost and treatment effectiveness in rheumatoid arthritis: results from the multicenter observational cohort study, FRANK Registry.

BACKGROUND: To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient's satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients. METHODS: This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient's satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment. RESULTS: This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, "very satisfied" and "satisfied" were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50-64 years; OR 0.91; 65-74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas. CONCLUSIONS: In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.

Predictive factors of non-treatment and non-persistence to osteoporosis medication after fragility hip fractures at 3 years after discharge: a multicentre, prospective cohort study in the northern Kyushu district of Japan.

We examined osteoporosis medication use and factors affecting persistence in 497 patients with fragility hip fractures. Only 25.5% of patients received continuous medication for 3 years, and 44.1% of patients received no treatment. Low Barthel index at discharge was a risk factor for both non-treatment and non-persistence to osteoporosis medication. PURPOSE: Fragility hip fractures (FHF) caused by osteoporosis decrease the quality of life and worsen life expectancy. Use of osteoporosis medication may be an efficient method in the prevention of secondary FHF. However, previous studies have reported low rates of osteoporosis medication and persistence after FHF. This study aimed to evaluate osteoporosis medication use and factors affecting persistence in patients with FHF in the northern Kyushu area of Japan. METHODS: A total of 497 FHF patients aged ≥ 60 years with a 3-year follow-up were included. We prospectively collected data from questionnaires sent every 6 months regarding compliance with osteoporosis medication. We compared baseline characteristics among three groups: no treatment (NT), no persistence (NP), and persistence (P), and conducted multivariable regression models to determine covariates associated with non-treatment (NT vs. NP/P) and non-persistence (NP vs. P). RESULTS: There were 219 (44.1%), 151 (30.4%), and 127 (25.5%) patients in the NT, NP, and P groups, respectively. Factors associated with non-treatment were male sex, chronic kidney disease, no previous osteoporosis treatment, and low Barthel index (BI) at discharge. The only factor associated with non-persistence was a low BI at discharge. Factors associated with a low BI at discharge were male sex, older age, trochanteric fracture, and surgical delay. CONCLUSION: Low BI at discharge is a risk factor for both non-treatment and non-persistence to osteoporosis medication. Therefore, appropriate interventions to improve BI may result in persistence to osteoporosis medication.

Spontaneous bilateral femoral neck fractures in a young male adult: a case report and literature review.

BACKGROUND: Simultaneous bilateral femoral neck fracture is a very rare condition, even in osteoporotic elderly individuals. We report an atypical case of a young male adult who developed simultaneous bilateral femoral neck fractures without previous trauma or overuse. CASE PRESENTATION: A 33-year-old man presented with discomfort in the bilateral groin, which had started 2 weeks previously. Bilateral femoral neck fractures were observed on a radiograph, and in addition, a fracture line was seen at the right subchondral region of the acetabulum using magnetic resonance imaging (MRI). Although the patient had no obvious risk factors associated with bone fragility, his bone mineral density measured using dual X-ray absorptiometry indicated severe osteoporosis (lumber spine: T score - 3.4 standard deviation [SD]; femoral neck: T score - 2.8 SD). Serum 25-hydroxyvitamin D level was deficient (19 ng/mL), which was considered to be partly due to non-sunlight exposure for 3 years owing to social withdrawal. Bilateral osteosynthesis was performed, considering his young age, although more than 2 weeks had passed since the onset of the fracture. Bone union and non-occurrence of osteonecrosis of the femoral head were confirmed via radiography and MRI 8 months after the surgery. CONCLUSIONS: Our case suggests that simultaneous non-traumatic bilateral femoral neck fractures can occur in healthy young men.