Safety of Biologics and Small Molecules for Inflammatory Bowel Diseases in Organ Transplant Recipients.

PURPOSE: This study aimed to evaluate the safety of biologics and small molecules for the treatment of inflammatory bowel diseases (IBD) in patients receiving antirejection therapies after organ transplants. MATERIALS AND METHODS: We reviewed the medical records of patients with IBD who received organ transplants at the Asan Medical Center between January 1989 and December 2021. We compared the parameters of patients receiving biologics or small molecules to those of patients without those therapies. RESULTS: This study included a total of 53 patients (ulcerative colitis, 41; Crohn's disease, 6; and gastrointestinal Behçet's disease, 6). Among them, 15 patients were receiving biologics or small molecules and 38 were not. During a mean follow-up of 119 months, the proportion of patients experiencing severe infections was significantly higher in those treated with biologics or small molecules than in those not treated. However, other safety outcomes (e.g., malignancies, adverse events, including organizing pneumonia or hepatic failure, and death) were not different between the two groups. Kaplan-Meier curve analysis revealed no significant difference in the safety outcome rate related to the use of biologics or small molecules. During follow-up, eight patients underwent bowel resections for IBD. The rate of bowel resection was not different between the two groups. CONCLUSION: The use of biologics or small molecules for patients with IBD who received organ transplants did not show a significant difference in safety outcomes. However, the possibility of severe infections must be considered.

Effects of dual-task resistance exercise on cognition, mood, depression, functional fitness, and activities of daily living in older adults with cognitive impairment: a single-blinded, randomized controlled trial.

BACKGROUND: Regular exercise is emphasized for the improvement of functional capacity and independence of older adults. This study aimed to compare the effects of a dual-task resistance exercise program and resistance exercise on cognition, mood, depression, physical function, and activities of daily living (ADL) in older adults with cognitive impairment. METHODS: A total of 44 older adults participated in the study. Participants were randomly allocated to an experimental group (n = 22) performing a dual-task resistance exercise program for cognitive function improvement and a control group (n = 22) performing a resistance exercise program. Both groups performed the exercise for 40 min per session, three times a week, for 6 weeks (18 sessions). Cognition, mood, depression, functional fitness, and ADL were quantified before and after the intervention using the Mini-Mental State Examination (MMSE), profile of mood states (POMS), geriatric depression scale (GDS), senior fitness test (SFT), and Korean version of ADL, respectively. RESULTS: There was a significant time and group interaction on the MMSE (p = 0.044). There were no significant time and group interactions in the POMS, GDS, SFT, or ADL. Cognitive function (p < 0.001), mood (p < 0.001), depression (p < 0.001), functional fitness (p < 0.001), and ADL (p < 0.001) significantly improved after dual-task resistance exercise, and cognitive function (p < 0.001), mood (p < 0.001), depression (p < 0.001), functional fitness (p < 0.001), and ADL (p < 0.001) significantly improved after resistance exercise. CONCLUSIONS: Dual-task resistance exercise is more effective than resistance exercise in improving cognitive function in older adults with cognitive impairment. Both dual-task resistance exercise and resistance exercise improves mood, depression, functional fitness, and ADL after the intervention. We propose using dual-task resistance exercises for cognitive and physical health management in the older adults with cognitive impairment. TRIAL REGISTRATION: This study was registered with the Clinical Research Information Service (WHO International Clinical Trials Registry Platform) (Registration ID, KCT0005389; Registration date, 09/09/2020).

PAUF as a Target for Treatment of High PAUF-Expressing Ovarian Cancer.

Pancreatic adenocarcinoma up-regulated factor (PAUF) plays an important role in tumor growth, metastasis, and immune evasion in the pancreatic tumor microenvironment, and recent studies suggest an association between PAUF expression and poor prognosis in ovarian cancer patients. The current study aimed 1) to characterize the potential tumor-promoting role of PAUF in ovarian cancer, using in vitro and in vivo models, including a PAUF-knockout OVCAR-5 cell line, and 2) to explore the potential therapeutic effects of an anti-PAUF antibody for ovarian cancer. Recombinant PAUF significantly increased tumor metastatic capacity (migration, invasion, and adhesion) in all the ovarian cancer cell lines tested, except for the OVCAR-5 cell line which expresses PAUF at a much higher level than the other cells. PAUF-knockout in the OVCAR-5 cell line led to apparently delayed tumor growth in vitro and in vivo. Furthermore, the administration of an anti-PAUF antibody exhibited notable sensitizing and synchronizing effects on docetaxel in mice bearing the OVCAR-5 xenograft tumors. Taken together, this study shows that the expression level of PAUF is an independent factor determining malignant behaviors of ovarian cancer and, for the first time, it suggests that PAUF may be a promising therapeutic target for high PAUF-expressing ovarian cancer.

Effects of Forest Healing Anti-Aging Program on Psychological, Physiological, and Physical Health of Older People with Mild Cognitive Impairment.

This study aimed to determine the effect of a forest healing anti-aging program on psychological, physiological, and physical health in older people with mild cognitive impairment (MCI). Twenty-two older people with MCI living in the city participated in a forest healing anti-aging program. Psychological indicators included the mini-mental state examination (MMSE), Beck depression inventory (BDI), profile of mood states (POMS), World Health Organization Quality of Life instrument (WHOQOL), and the Pittsburgh sleep quality index (PSQI). Physiological indicators included vital signs, body composition, and blood analysis. Physical indicators included the senior fitness test (SFT), muscle strength, spatiotemporal parameter of gait, static balance, and dynamic balance. Psychological, physiological, and physical indicators were evaluated at first and second pre-measurement, post-measurement, and one-month follow-up. MMSE, BDI, POMS, WHOQOL, body composition, blood analysis, SFT, muscle strength, spatiotemporal parameter of gait, and dynamic balance were significantly different between pre- and post-measurement. Beck depression inventory, POMS, WHOQOL, PSQI, SFT, muscle strength (elbow flexor muscle, knee extensor muscle), spatiotemporal parameter of gait significantly improved continually until the one-month follow-up. In conclusion, the forest healing program had a positive effect on the psychological, physiological, and physical health of older people with MCI.

Regulation of bone metabolism by megakaryocytes in a paracrine manner.

Megakaryocytes (MKs) play key roles in regulating bone metabolism. To test the roles of MK-secreted factors, we investigated whether MK and promegakaryocyte (pro-MK) conditioned media (CM) may affect bone formation and resorption. K562 cell lines were differentiated into mature MKs. Mouse bone marrow macrophages were differentiated into mature osteoclasts, and MC3T3-E1 cells were used for osteoblastic experiments. Bone formation was determined by a calvaria bone formation assay in vivo. Micro-CT analyses were performed in the femurs of ovariectomized female C57B/L6 and Balb/c nude mice after intravenous injections of MK or pro-MK CM. MK CM significantly reduced in vitro bone resorption, largely due to suppressed osteoclastic resorption activity. Compared with pro-MK CM, MK CM suppressed osteoblastic differentiation, but stimulated its proliferation, resulting in stimulation of calvaria bone formation. In ovariectomized mice, treatment with MK CM for 4 weeks significantly increased trabecular bone mass parameters, such as bone volume fraction and trabecular thickness, in nude mice, but not in C57B/L6 mice. In conclusion, MKs may secrete anti-resorptive and anabolic factors that affect bone tissue, providing a novel insight linking MKs and bone cells in a paracrine manner. New therapeutic agents against metabolic bone diseases may be developed from MK-secreted factors.

SLIT3 regulates endochondral ossification by ß-catenin suppression in chondrocytes.

Previously, we noted that SLIT3, slit guidance ligand 3, had an osteoprotective role with bone formation stimulation and bone resorption suppression. Additionally, we found that global Slit3 KO mice had smaller long bone. Skeletal staining showed short mineralized length in the newborn KO mice and wide hypertrophic chondrocyte area in the embryo KO mice, suggesting delayed chondrocyte maturation. The recombinant SLIT3 did not cause any change in proliferation of ATDC5 cells, but stimulated expressions of chondrocyte differentiation markers, such as COL2A1, SOX9, COL10A1, VEGF, and MMP13 in the cells. SLIT3 suppressed ß-catenin activity in the cells, and activation of Wnt/ß-catenin signaling by lithium chloride attenuated the SLIT3-stimulated differentiation markers. ATDC5 cells expressed only ROBO2 among their 4 isotypes, and the Robo2 knock-down with its siRNA reversed the SLIT3-stimulated differentiated markers in chondrocytes. Taken together, these indicate that SLIT3/ROBO2 promotes chondrocyte maturation via the inhibition of ß-catenin signaling.

Application of computer-aided diagnosis in breast ultrasound interpretation: improvements in diagnostic performance according to reader experience.

PURPOSE: The purpose of this study was to evaluate the usefulness of applying computer-aided diagnosis (CAD) to breast ultrasound (US), depending on the operator's experience with breast imaging. METHODS: Between October 2015 and January 2016, two experienced readers obtained and analyzed the grayscale US images of 200 cases according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon and categories. They additionally applied CAD (S-Detect) to analyze the lesions and made a diagnostic decision subjectively, based on grayscale US with CAD. For the same cases, two inexperienced readers analyzed the grayscale US images using the BI-RADS lexicon and categories, added CAD, and came to a subjective diagnostic conclusion. We then compared the diagnostic performance depending on the operator's experience with breast imaging. RESULTS: The sensitivity values for the experienced readers, inexperienced readers, and CAD (for experienced and inexperienced readers) were 91.7%, 75%, 75%, and 66.7%, respectively. The specificity values for the experienced readers, inexperienced readers, and CAD (for experienced and inexperienced readers) were 76.6%, 71.8%, 78.2%, and 76.1%, respectively. When diagnoses were made subjectively in combination with CAD, the specificity significantly improved (76.6% to 80.3%) without a change in the sensitivity (91.7%) in the experienced readers. After subjective combination with CAD, the sensitivity and specificity improved in the inexperienced readers (75% to 83.3% and 71.8% to 77.1%). In addition, the area under the curve improved for both the experienced and inexperienced readers (0.84 to 0.86 and 0.73 to 0.8) after the addition of CAD. CONCLUSION: CAD is more useful for less experienced readers. Combining CAD with breast US led to improved specificity for both experienced and inexperienced readers.

Diagnostic Performance of and Breast Tissue Changes at Early Breast MR Imaging Surveillance in Women after Breast Conservation Therapy.

Purpose To investigate the diagnostic performance and tissue changes in early (1 year or less) breast magnetic resonance (MR) imaging surveillance in women who underwent breast conservation therapy for breast cancer. Materials and Methods This prospective study was approved by the institutional review board, and written informed consent was obtained. Between April 2014 and June 2016, 414 women (mean age, 51.5 years; range, 21-81 years) who underwent 422 early surveillance breast MR imaging examinations (median, 6.0 months; range, 2-12 months) after breast conservation therapy were studied. The cancer detection rate, positive predictive value of biopsy, sensitivity, specificity, accuracy, and area under the curve of surveillance MR imaging, mammography, and ultrasonography (US) were assessed. Follow-up was also obtained in 95 women by using positron emission tomography (PET)/computed tomography (CT). Background parenchymal enhancement (BPE) changes in the contralateral breast were assessed according to adjuvant therapy by using the McNemar test. Results Of 11 detected cancers, six were seen at MR imaging only, one was seen at MR imaging and mammography, two were seen at MR imaging and US, one was seen at mammography only, and one was seen at PET/CT only. Three MR imaging-depicted cancers were observed at the original tumor bed, and two MR imaging-depicted cancers were observed adjacent to the original tumor. Among two false-negative MR imaging diagnoses (two cases of ductal carcinoma in situ), one cancer had manifested as calcifications at mammography without differentiated enhancement at MR imaging, and the other cancer was detected at PET/CT, but MR imaging results were negative because of marked BPE, which resulted in focal lesion masking. The positive predictive value of biopsy and the sensitivity, specificity, accuracy, and area under the curve for MR imaging were 32.1% (nine of 28), 81.8% (nine of 11), 95.1% (391 of 411), 94.7% (400 of 422), and 0.88, respectively. The sensitivity of surveillance MR imaging (81.8%; 95% confidence interval [CI]: 48.2%, 97.7%) was higher than that of mammography (18.2%; 95% CI: 2.3%, 51.8%) and US (18.2%; 95% CI: 2.3%, 51.8%), with an overlap in CIs. The BPE showed a significant decrease in the group of patients who received adjuvant chemotherapy (43 BPE decreases and four BPE increases) and the group of patients who received hormone therapy (55 BPE decreases and two BPE increases) (P < .0001 for both). Conclusion Early MR imaging surveillance after breast conservation therapy can be useful in patients who have breast cancer, with superior sensitivity compared with that of mammography and US. The BPE tends to be decreased at short-term follow-up MR imaging in patients who receive adjuvant therapy. © RSNA, 2017.

Radiation dose affected by mammographic composition and breast size: first application of a radiation dose management system for full-field digital mammography in Korean women.

BACKGROUND: Relative to Western women, Korean women show several differences in breast-related characteristics, including higher rates of dense breasts and small breasts. We investigated how mammographic composition and breast size affect the glandular dose during full-field digital mammography (FFDM) in Korean women using a radiation dose management system. METHODS: From June 1 to June 30, 2015, 2120 FFDM images from 560 patients were acquired and mammographic breast composition and breast size were assessed. We analyzed the correlations of patient age, peak kilovoltage (kVp), current (mAs), compressed breast thickness, compression force, mammographic breast composition, and mammographic breast size with the mean glandular dose (MGD) of the breast using a radiation dose management system. The causes of increased radiation were investigated, among patients with radiation doses above the diagnostic reference level (4th quartile, ≥75%). RESULTS: The MGD per view of 2120 images was 1.81 ± 0.70 mGy. In multivariate linear regression analysis, age was negatively associated with MGD (p < 0.05). The mAs, kVp, compressed breast thickness, and mammographic breast size were positively associated with MGD (p < 0.05). The "dense" group had a significantly higher MGD than the "non-dense" group (p < 0.05). Patients with radiation dose values above the diagnostic reference value had large breasts of dense composition. CONCLUSIONS: Among Korean women, patients with large and dense breasts should be more carefully managed to ensure that a constant radiation dose is maintained.

Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer.

Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment (TME) with a profound immune infiltrate populated by a significant number of myeloid-derived suppressor cells (MDSCs). MDSCs have been increasingly recognized for their role in immune evasion and cancer progression as well as their potential as a target for immunotherapy. However, not much is known about the mechanisms regulating their behavior and function in the pancreatic TME. Here we report that pancreatic adenocarcinoma up-regulated factor (PAUF), a soluble protein involved in pancreatic tumorigenesis and metastasis, plays a role as an enhancer of tumor-infiltrating MDSC and its functional activity. We show that PAUF enhanced the accumulation of MDSCs in the spleen and tumor tissues of PAUF-overexpressing tumor cell-injected mice. In addition, PAUF was found to enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway, which was demonstrated by PAUF-induced increased levels of arginase, nitric oxide (NO), and reactive oxygen species (ROS). The role of PAUF in modulating the functional properties of MDSCs was further demonstrated by the use of a PAUF-neutralizing antibody that caused a decreased number of tumor-infiltrating MDSCs and reduced MDSC immunosuppressive activity. The observations made in mice were confirmed in human pancreatic cancer patient-derived MDSCs, supporting the clinical relevance of our findings. Collectively, we conclude that the PAUF is a powerful and multifunctional promoter of tumor growth through increase and functional activation of MDSCs, suggesting therapeutic potential for targeting PAUF in pancreatic cancers.

Free Fatty Acid Receptor 4 (GPR120) Stimulates Bone Formation and Suppresses Bone Resorption in the Presence of Elevated n-3 Fatty Acid Levels.

Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4(-/-)) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1(Tg+)) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4(-/-) and fat-1(Tg+) mice over two generations to generate four genotypes of mice littermates: Ffar4(+/+);fat-1(Tg-), Ffar4(+/+);fat-1(Tg+), Ffar4(-/-);fat-1(Tg-), and Ffar4(-/-);fat-1(Tg+). Female and male littermates were included in ovariectomy- and high-fat diet-induced bone loss models, respectively. Female fat-1(Tg+) mice decreased bone loss after ovariectomy both by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption than their wild-type littermates, only when they had the Ffar4(+/+) background, but not the Ffar4(-/-) background. In a high-fat diet-fed model, male fat-1(Tg+) mice had higher bone mass resulting from stimulated bone formation and reduced bone resorption than their wild-type littermates, only when they had the Ffar4(+/+) background, but not the Ffar4(-/-) background. In vitro studies supported the role of FFA4 as n-3 FA receptor in bone metabolism. In conclusion, FFA4 is a dual-acting factor that increases osteoblastic bone formation and decreases osteoclastic bone resorption, suggesting that it may be an ideal target for modulating metabolic bone diseases.

Perfusion Parameters in Dynamic Contrast-enhanced MRI and Apparent Diffusion Coefficient Value in Diffusion-weighted MRI:: Association with Prognostic Factors in Breast Cancer.

RATIONALE AND OBJECTIVES: To evaluate the association of prognostic factors and subtypes of breast cancer with perfusion parameters in dynamic contrast-enhanced magnetic resonance imaging and apparent diffusion coefficient (ADC) values in diffusion-weighted magnetic resonance imaging. MATERIALS AND METHODS: Quantitative perfusion parameters (constant of transfer from plasma to interstitium, constant of transfer from the interstitium to the plasma, extravascular/extracellular volume per unit of volume of tissue [ve], and initial area under the concentration curve [iAUC]) and ADC values in the entire tumor volume of 52 invasive ductal carcinomas were obtained using histogram analysis. Four measures (25th percentile, mean, median, 75th percentile) were calculated for each parameter and the ADC value. Associations of perfusion parameters and ADC values with prognostic factors and tumor subtypes were analyzed. RESULTS: Among perfusion parameters, iAUCmean and iAUCmedian were greater in tumors larger than 2 cm (8.23 ± 2.33, 8.64 ± 2.67 × 10(4)) than in those smaller than 2 cm (6.99 ± 1.92, 7.04 ± 2.15 × 10(4); P = 0.046, 0.023). Ve median was higher in tumors with progesterone receptor (PR) positivity (0.54 ± 0.18) than in those with PR negativity (0.44 ± 0.1, P = 0.041). There were higher ADCmean and ADCmedian in tumors with human epidermal growth factor receptor 2 (HER2) positivity (1.306 and 1.278 × 10(-3)mm(2)/s) than in those with HER2 negativity (1.078 and 1.053 × 10(-3)mm(2)/s; P = 0.012 and 0.020). Higher ADCmean and ADCmedian were observed in HER2-enriched type (1.404 and 1.378 × 10(-3)mm(2)/s) than in luminal type (1.096 and 1.073 × 10(-3)mm(2)/s; P = 0.030 and 0.045). CONCLUSIONS: Among perfusion parameters, iAUC was associated with tumor size and ve median was associated with PR positivity. Mean and median ADC values showed positive correlation with HER2-positive and HER2-enriched tumors.

Skeletal analysis and differential gene expression in Runx2/Osterix double heterozygous embryos.

The transcription factors, Runx2 and Osterix (Osx), act downstream in the BMP2 pathway, and they are essential for osteoblast differentiation and bone formation. While Runx2 expression is normal in Osx-null mice, Osx is not expressed in Runx2-null mice, indicating that Osx acts downstream of Runx2 during bone formation. Runx2 and Osx are also independently regulated during bone formation. To define the unknown correlation between Runx2 and Osx in the regulation of bone formation, we analyzed the bone of Runx2/Osx double heterozygotes generated by mating heterozygous Runx2 and Osx mice and elucidated the differential gene expressions due to the lack of Runx2 and Osx in bone. Compared to the Runx2 and Osx heterozygous embryos, Runx2/Osx double heterozygous embryos showed reduced bone length in the humerus and femur as well as hypoplastic or complete absence of the maxillary and palatine shelf, presphenoid bone, zygomatic bone, and tympanic ring. Severe inward bending was observed in the ribs and humerus. Histological analysis showed an expanded region of hypertrophic chondrocytes and a reduced area of mineralized bones in the Runx2/Osx double heterozygous embryos. DNA microarray analysis of the calvaria of embryos allowed gene classification based on similarities in the upregulated and downregulated expression patterns. Clusters 1 and 2 include 68 downregulated genes and 18 upregulated genes, respectively, in the Runx2/Osx double heterozygous embryos. Finally, the skeletal analysis and gene expression profiles obtained by clustering may facilitate the understanding of the correlation between Runx2 and Osx in skeletal development.

Background parenchymal enhancement in breast MRIs of breast cancer patients: impact on tumor size estimation.

OBJECTIVE: To evaluate whether the degree of background parenchymal enhancement affects the accuracy of tumor size estimation based on breast MRI. METHODS: Three hundred and twenty-two patients who had known breast cancer and underwent breast MRIs were recruited in our study. The total number of breast cancer cases was 339. All images were assessed retrospectively for the level of background parenchymal enhancement based on the BI-RADS criteria. Maximal lesion diameters were measured on the MRIs, and tumor types (mass vs. non-mass) were assessed. Tumor size differences between the MRI-based estimates and estimates based on pathological examinations were analyzed. The relationship between accuracy and tumor types and clinicopathologic features were also evaluated. RESULTS: The cases included minimal (47.5%), mild (28.9%), moderate (12.4%) and marked background parenchymal enhancement (11.2%). The tumors of patients with minimal or mild background parenchymal enhancement were more accurately estimated than those of patients with moderate or marked enhancement (72.1% vs. 56.8%; p=0.003). The tumors of women with mass type lesions were significantly more accurately estimated than those of the women with non-mass type lesions (81.6% vs. 28.6%; p<0.001). The tumor of women negative for HER2 was more accurately estimated than those of women positive for HER2 (72.2% vs. 51.6%; p=0.047). CONCLUSION: Moderate and marked background parenchymal enhancement is related to the inaccurate estimation of tumor size based on MRI. Non-mass type breast cancer and HER2-positive breast cancer are other factors that may cause inaccurate assessment of tumor size.

Solitary fibrous tumor of the pleura manifesting as an air-containing cystic mass: radiologic and histopathologic correlation.

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that typically presents as a well-defined lobular soft tissue mass commonly arising from the pleura. We report an extremely rare case of an SFT containing air arising from the right major fissure in a 58-year-old woman. Chest CT showed an ovoid air-containing cystic mass with an internal, homogeneously enhancing solid nodule. To our knowledge, this is the first case in the literature. The histopathologic findings were correlated with the radiologic findings, and the mechanism of air retention within the tumor is discussed.

Reduction of Zygomatic Fractures Using the Carroll-Girard T-bar Screw.

Zygomatic fractures are the second most common facial bone fractures encountered and treated by plastic surgeons. Stable fixation of fractured fragments after adequate exposure is critical for ensuring three-dimensional anatomic reduction. Between January 2008 and December 2010, 17 patients with zygomatic fractures were admitted to our hospital; there were 15 male and 2 female patients. The average age of the patients was 41 years (range, 19 to 75 years). We exposed the inferior orbital rim and zygomatic complex through a lateral brow, intraoral, and subciliary incisions, which allowed for visualization of the bone, and then the fractured parts were corrected using the Carroll-Girard T-bar screw. Postoperative complications such as malar asymmetry, diplopia, enophthalmos, and postoperative infection were not observed. Lower eyelid retraction and temporary ectropion occurred in 1 of the 17 patients. Functional and cosmetic results were excellent in nearly all of the cases. In this report, we describe using the Carroll-Girard T-bar screw for the reduction of zygomatic fractures. Because this instrument is easy to use and can rotate to any direction and vector, it can be used to correct displaced zygomatic bone more accurately and safely than other devices, without leaving facial scars.

TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition.

Although recent clinical studies have suggested a possible role for sclerostin, a secreted Wnt antagonist, in the pathogenesis of postmenopausal osteoporosis, the detailed mechanisms how estrogen deficiency regulates sclerostin expression have not been well-elucidated. Bilateral ovariectomy or a sham operation in female C57BL/6 mice and BALB/c nude mice was performed when they were seven weeks of age. The C57BL/6 mice were intraperitoneally injected with phosphate-buffered serum (PBS), 5 µg/kg ß-estradiol five times per week for three weeks, or 10 mg/kg TNF-α blocker three times per week for three weeks. Bony sclerostin expression was assessed by immunohistochemistry staining in their femurs. The activity and expression of myocyte enhancer factors 2 (MEF2), which is essential for the transcriptional activation of sclerostin, in rat UMR-106 osteosarcoma cells were determined by luciferase reporter assay and western blot analysis, respectively. Bony sclerostin expression was stimulated by estrogen deficiency and it was reversed by estradiol supplementation. When the UMR-106 cells were treated with well-known, estrogen-regulated cytokines, only TNF-α, but not IL-1 and IL-6, increased the MEF2 activity. Consistently, TNF-α also increased the nuclear MEF2 expression. Furthermore, the TNF-α blocker prevented the stimulation of bony sclerostin expression by ovariectomy. We also found that there was no difference in sclerostin expression between ovariectomized nude mice and sham-operated nude mice. In conclusion, these results suggest that TNF-α originating from T cells may be at least in part responsible for stimulating the sclerostin expression observed in an estrogen-deficient condition.