miR-582-5p targets Skp1 and regulates NF-κB signaling-mediated inflammation.

A well-tuned inflammatory response is crucial for an effective immune process. Nuclear factor-kappa B (NF-κB) is a key mediator of inflammatory and innate immunity responses, and its dysregulation is closely associated with immune-related diseases. MicroRNAs (miRNAs) are important inflammation modulators. However, miRNA-regulated mechanisms that implicate NF-κB activity are not fully understood. This study aimed to identify a potential miRNA that could modulate the dysregulated NF-κB signaling during inflammation. We identified miR-582-5p that was significantly downregulated in inflamed murine adipose tissues and RAW264.7 cells. S-phase kinase-associated protein 1 (SKP1), a core component of an E3 ubiquitin ligase that regulates the NF-κB pathway, was proposed as a biological target of miR-582-5p by using TargetScan. The binding of miR-582-5p to a 3'-untranslated region site on Skp1 was confirmed using a dual-luciferase reporter assay; in addition, transfection with a miR-582-5p mimic suppressed SKP1 expression in RAW264.7 cells. Importantly, exogenous miR-582-5p attenuated the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 through suppressing the degradation of the NF-κB inhibitor alpha, followed by the nuclear translocation of NF-κB. Therefore, exogenously applied miR-582-5p can attenuate the NF-κB signaling pathway via targeting Skp1; this provides a prospective therapeutic strategy for treating inflammatory and immune diseases.

Abaloparatide dose-dependently increases bone mineral density in postmenopausal women with osteoporosis: a phase 2 study.

INTRODUCTION: This study aimed to determine the efficacy of abaloparatide in increasing bone mineral density (BMD) and its safety in postmenopausal Japanese women with osteoporosis. MATERIALS AND METHODS: Randomized, double-blind, placebo-controlled, dose-finding study of abaloparatide in postmenopausal Japanese women at high fracture risk. The primary endpoint was the change in lumbar spine (LS) BMD from baseline at the last visit after daily subcutaneous injections of placebo or 40 or 80 µg abaloparatide. Other endpoints included time-course changes in LS BMD at 12, 24, and 48 weeks, in total hip (TH) and femoral neck (FN) BMDs, and in bone turnover markers. RESULTS: Increases in LS BMD with 40 and 80 µg abaloparatide were significantly higher than that with placebo (6.6% and 11.5%, respectively), with significant between-group differences for the abaloparatide groups (4.9%). TH BMD increased by 0.4%, 1.6%, and 2.9% and FN BMD increased by 0.6%, 1.5%, and 2.4% in the placebo and 40 and 80 µg abaloparatide groups, respectively. Serum PINP rapidly increased by 67.3% and 140.7% and serum CTX slowly increased by 16.4% and 34.5% in the 40 and 80 µg abaloparatide groups, respectively. Although more adverse events were observed in the abaloparatide groups, they were mild to moderate and not dose dependent. CONCLUSION: In postmenopausal Japanese women with osteoporosis at high fracture risk, abaloparatide for 48 weeks dose-dependently increased LS, TH, and FN BMDs, supporting further investigation with 80 µg abaloparatide for the treatment of osteoporosis in this population. TRIAL REGISTRATION NUMBER: JapicCTI-132381.

SPOCK1 induces adipose tissue maturation: New insights into the function of SPOCK1 in metabolism.

SPOCK1 is a calcium-binding matricellular proteoglycan that has been extensively studied in several cancer cells. Previously, we generated a mouse line overexpressing SPOCK1 (Spock1-Tg mouse) and showed that SPOCK1 might play an important role in drug-induced gingival overgrowth, indicating that it possesses physiological functions in non-cancer diseases as well. Although SPOCK1 was reported to be secreted from human adipocytes, its role in adipocyte physiology has not been addressed yet. In this study, SPOCK1 protein expression was confirmed in pancreas, adipose tissues, spleen, and liver of normal diet (ND)-fed mice. Interestingly, SPOCK1 was up-regulated in the pancreas and adipose tissues of the high-fat diet (HFD)-fed mice. Spock1-Tg mice fed with ND showed increased maturation in epididymal and inguinal adipose tissues. In addition, Spock1 overexpression strongly decreased expression of UCP-1 in adipose tissues, suggesting that SPOCK1 might regulate thermogenic function through suppression of UCP-1 expression. Finally, exogenous SPOCK1 treatment directly accelerated the differentiation of 3T3-L1 adipocytes, accompanied by the up-regulation of adipocyte differentiation-related gene expression. In conclusion, we demonstrated for the first time that SPOCK1 induced adipocyte differentiation via the up-regulation of adipogenesis-related genes.

Adipose tissue complement factor B promotes adipocyte maturation.

OBJECTIVES: It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system-related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism. METHODS: We investigated the expression level of complement system-related genes in adipocytes. To understand the role of CfB in adipocyte, we performed Cfb overexpression in 3T3-L1 preadipocytes and generated adipocyte-specific Cfb transgenic mice. RESULTS: Cfb expression was markedly enhanced in 3T3-L1 adipocytes co-cultured with macrophages following endotoxin stimulation. In Cfb-overexpressing cells, the expression of adipocyte differentiation/maturation-related genes encoding peroxisome proliferator-activated receptor γ (Pparγ), adipocyte Protein 2 and perilipin was significantly enhanced. Cfb transgenic mice showed a marked increase in the expression of genes encoding Pparγ, perilipin, sterol regulatory element-binding protein 1 c, and Cd36 in the subcutaneous adipose tissue. CONCLUSIONS: CfB plays a crucial role in late-phase of adipocyte differentiation and subsequent lipid droplet formation.

Metabolic Endotoxemia-Activated Macrophages Promote Pancreatic ß Cell Death via IFNß-Xaf1 Pathway.

Metabolic endotoxemia has been implicated in the pathogenesis of type 2 diabetes. In addition to adipose tissue inflammation, inflammatory cell infiltration is also observed in islets, although its effect on islets is largely unknown. We hypothesized that macrophage infiltration into islets leads to impairment of α or ß cell function, which ultimately act to exacerbate the pathophysiology of diabetes. Gene expression in a murine α cell line, αTC1, and ß cell line, ßTC6, was investigated by DNA microarray after co-culturing the cells with a murine macrophage cell line, RAW 264.7, in the presence or absence of bacterial endotoxin. Among the genes showing highly upregulated expression, genes specifically upregulated only in ß cells were evaluated to determine the roles of the gene products on the cellular function of ß cells. In both α and ß cells, expression of type I interferon-responsive genes was highly upregulated upon endotoxin stimulation. Among these genes, expression of the X-linked inhibitor of apoptosis (Xiap)-associated factor 1 (Xaf1) gene, which is associated with the induction of apoptosis, was specifically enhanced in ß cells by endotoxin stimulation. This upregulation appeared to be mediated by macrophage-derived interferon ß (IFNß), as endotoxin-stimulated macrophages produced higher amounts of IFNß, and exogenous addition of IFNß into ßTC6 cultures resulted in increased Xaf1 protein production and cleaved caspase 3, which accelerated ß-cell apoptosis. Macrophages activated by metabolic endotoxemia infiltrated into islets and produced IFNß, which induced ß-cell apoptosis by increasing the expression of Xaf1.

Changes of Doublecortin-Immunoreactive Cells from the Acute Phase to Chronic Phase After Transient Global Brain Ischemia in Rat Cingulate Cortex.

Doublecortin (DCX)-immunoreactive (-ir) cells play important roles in adult cortical remodeling. We previously reported that DCX-ir cells decrease after transient global brain ischemia (GBI) in the cingulate cortex (Cg) of rats. In the present study, we examined the changes of DCX-ir cells from the acute to the chronic phase after GBI in rats. Transient GBI was induced by a four-vessel occlusion model as described previously. Thirty-six rats were divided into six groups: day 7 after sham operation (Group Sham+A), day 7 after 3 min GBI (Group GBI3+A), day 7 after 10 min GBI (Group GBI10+A), day 90 after sham operation (Group Sham+C), day 90 after 3 min GBI (Group GBI3+C), and day 90 after 10 min GBI (Group GBI10+C). The numbers of DCX-ir cells per unit area (mm2) were investigated in the anterior cingulate cortex (ACC) and retrosplenial cortex (RS). A two-way factorial analysis of variance regarding the time of GBI (sham, GBI3, GBI10) or the period after GBI (day 7, day 90) was employed in each area. Regarding the time of GBI, there were significant differences in both the ACC and the RS (p < 0.001, respectively). Regarding the period after GBI, there was no significant difference in the ACC, whereas a significant difference was found in the RS (p = 0.005). In each area and in each phase, the numbers did not change in GBI3 (one-way ANOVA followed by a Tukey test) and decreased in GBI10 (p < 0.005). The numbers in the RS from the acute phase to chronic phase did not change in the sham and GBI3, and decreased in GBI10 (independent t-test, p < 0.001). However, histochemical staining with Fluoro-Jade B suggested that neuronal cell death did not occur in both the ACC and the RS in all groups. The present findings indicate that the cortical remodeling potential in the Cg decreases in the acute phase after GBI, and continues to decrease until the chronic phase.

Roles of venovenous anastomosis and umbilical cord insertion abnormalities in birthweight discordance in monochorionic-diamniotic twin pregnancies without twin-twin transfusion syndrome.

AIM: We evaluated risk factors for birthweight discordance in monochorionic diamniotic (MCDA) twin pregnancies without twin-twin transfusion syndrome (TTTS). METHODS: We investigated all MCDA twin placentas injected with colored dye at our institution between 2007 and 2015. We excluded pairs of twins with TTTS, fetal demise, or severe fetal malformation. All pairs of twins were assigned to the discordant group (birthweight discordance ≥ 25%) or the concordant group (birthweight discordance < 25%). In each pair of twins, we described vascular anastomoses as either arterioarterial, venovenous (VV), or arterial-venous, and abnormal umbilical cord insertion as either marginal or velamentous. We also recorded placental sharing discordance. RESULTS: A total of 150 placentas were analyzed. The incidence of VV anastomosis in the discordant group (40%) was significantly higher than that in the concordant group (12%, P = 0.005). Unilateral abnormal umbilical cord insertion was significantly more common in the discordant group (85%) than in the concordant group (38%, P < 0.001). Placental sharing discordance was seen more frequently in the discordant group than in the concordant group. Multiple logistic analysis revealed that VV anastomosis (odds ratio: 4.7; 95% confidence interval: 1.2-18.6, P < 0.01) and unilateral abnormal umbilical cord insertion of the smaller twin (odds ratio: 5.7; 95% confidence interval: 1.4-22.9, P < 0.01) were independent risk factors for birthweight discordance. CONCLUSION: VV anastomoses and unilateral abnormal umbilical cord insertion of the smaller twin are independent risk factors for birthweight discordance in MCDA twin pregnancies without TTTS.

A Perifascial Areolar Tissue Graft With Topical Administration of Basic Fibroblast Growth Factor for Treatment of Complex Wounds With Exposed Tendons and/or Bones.

The management of wounds with tendon and/or bone exposure is challenging because of the insufficient blood supply to the wound bed. We describe our experience with 19 patients using a perifascial areolar tissue (PAT) graft with topical administration of basic fibroblast growth factor (bFGF) in the treatment of complex wounds with exposed tendons and/or bones in the extremities. Using a PAT graft is minimally invasive and technically easy, and the donor site is relatively preserved. However, PAT grafts for the treatment of a complex wound with large areas of exposed tendons and/or bones have sometimes failed to survive because of insufficient vascularization of the wound bed. Therefore, topical administration of bFGF, which promotes angiogenesis, was added to the graft. All grafts showed good graft survival and successfully covered the tendons and bones. Topical administration of bFGF accelerated vascularization in the PAT graft and facilitated wound healing by increasing the blood supply to the wound bed and achieved success with the PAT graft. In conclusion, using a PAT graft with topical administration of bFGF is a suitable option for the treatment of complex wounds with a large proportion of exposed tendons and/or bones. With minimal damage to the tissues near the wound, the PAT graft can be a useful option for limb salvage and could become a valuable tool for reconstructive surgeons.

IL-17A synergistically enhances TNFα-induced IL-6 and CCL20 production in 3T3-L1 adipocytes.

Interleukin-17A (IL-17A) is known to induce inflammatory responses and to be involved in the pathogenesis of not only autoimmune diseases, but also several metabolic and infectious diseases. In this study, IL-17A is shown to induce IL-6 expression in 3T3-L1 mature adipocytes. Interestingly, we found that IL-17A synergistically amplified TNFα-induced secretion of IL-6 and upregulation of IL-17RA expression in 3T3-L1 adipocytes. Its synergistic effects on IL-6 production were inhibited by pre-treatment with inhibitors of IκBα and JNK. Furthermore, IL-17A cooperatively enhanced LPS-mediated IL-6 production in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. In addition, IL-17A also enhanced CCL20 production in 3T3-L1 adipocytes stimulated with TNFα or co-cultured with LPS-stimulated RAW macrophages. In high-fat diet-fed mouse epididymal adipose tissues, IL-17RA and RORγt mRNA levels were significantly increased and the serum level of CCL20 was also upregulated. Taken together, these data show that, in adipose tissues, IL-17A contributes to exacerbating insulin resistance-enhancing IL-6 production and promotes the infiltration of Th17 cells in cooperation with TNFα; these findings represent a novel hypothesis for the association between IL-17A-producing cells and type 2 diabetes.

Associated anomalies in congenital diaphragmatic hernia: perinatal characteristics and impact on postnatal survival.

OBJECTIVE: We aimed to investigate the clinical characteristics and postnatal outcomes of fetuses with congenital diaphragmatic hernia (CDH) and additional anomalies. MATERIALS AND METHODS: We reviewed the charts of fetuses with CDH managed between 2005 and 2013. Patients were divided into complex and isolated groups based on the presence of additional anomalies. We analyzed the respective polyhydramnios, liver herniation, stomach position, lung to thorax transverse area ratio (LTR), and prognoses of the two groups. The survival rates of both groups were assessed based on the LTR as well as on stomach and liver positions. RESULTS: CDH was diagnosed in 65 fetuses, and additional anomalies were found in 23. The incidences of liver herniation, polyhydramnios, and death were significantly higher, and LTR was significantly lower, in the complex group. The mortality rate of fetuses with a LTR <0.08 was lower than that of fetuses with a LTR of ≥0.08 in the complex group. Further, the survival rate of fetuses with intrathoracic liver was lower than those without liver herniation. CONCLUSIONS: The prognosis of complex CDH is poor. This may result from both the associated anomalies and the severity of CDH itself. Even in complex CDHs, intrathoracic liver and LTR values are useful in estimating postnatal outcome.

Correction of Late Posttraumatic Enophthalmos Using an Antral Balloon.

Enophthalmos is the posterior displacement of the ocular globe within the bony orbit. Correction of late posttraumatic enophthalmos is one of the most challenging surgical procedures. We have performed a corrective procedure for late enophthalmos using an antral balloon, with or without minimal bone grafting. All orbital contents were separated from the bone fragments, infraorbital nerve, and mucosa of the maxillary antrum. The remaining orbital floor was fractured by the surgeon's digital pressure from the maxillary antrum. The antral balloon was placed in the maxillary antrum and inflated under direct vision from inside the orbit. After a consolidation period, the patient underwent antral balloon removal. A total of 5 patients underwent repair of late enophthalmos using this antral balloon technique. The median time from initial injury was 14 months (range, 6-90 months). The median antral balloon placement duration was 76 days (range, 53-106 days). Satisfactory symmetries were achieved in 4 patients. Mild residual enophthalmos remained in 1 patient, who had an orbital framework deformity and was missing the entire orbital bony floor preoperatively and who required simultaneous bone grafting. The ideal indication for our technique was the need for orbital floor reconstruction, without an orbital framework deformity. This technique could avoid autogenous bone grafting or permanent alloplastic implantation, which may cause a foreign body reaction, chronic inflammation, and migration. We believe that our new technique is one of the least invasive corrective procedures for late posttraumatic enophthalmos.

Monochorionic monozygotic twin pregnancy complicated with twin-twin transfusion syndrome presenting with an obvious lambda sign in the first trimester.

In this report, we present a case of twin-twin transfusion syndrome in the presence of the thick dividing wall of each sac in dichorionic twins. The dichorionic diagnosis was based on the presence of the lambda sign at the first-trimester ultrasound evaluation. In addition to fetoscopic and pathological investigation, DNA typing confirmed that the twin set was monochorionic and monozygotic. This case illustrates that although extremely uncommon, the presence of lambda sign does not exclude monochorionic pregnancy.

In utero resolution of microcystic congenital cystic adenomatoid malformation after prenatal betamethasone therapy: A report of three cases and a literature review.

Fetal congenital cystic adenomatoid malformation (CCAM) can progress to nonimmune hydrops, and the mortality rate of CCAM with hydrops is reported to be nearly 100%. We describe three microcystic CCAM cases in which the fetal condition improved after maternal betamethasone therapy. The median gestational age at steroid administration was 23 5/7 weeks' gestation. The CCAM decreased in size in all cases. Our series showed a 100% hydrops resolution rate (2/2) and a 100% survival rate (3/3). Our experience suggests the efficacy of betamethasone treatment on fetuses with microcystic CCAM who have fluid collection or are at risk of developing hydrops.

The inflammation-lipocalin 2 axis may contribute to the development of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is an important risk factor for coronary heart disease, and previous studies indicated the involvement of low-grade inflammation in the pathogenesis of CKD. METHODS: The study was designed to (i) identify and confirm genes and their products upregulated in mesangial cells cocultured with endotoxin-stimulated macrophages and (ii) determine the clinical relevance of genes and proteins upregulated in mesangial cells under inflammatory conditions by an epidemiological approach. RESULTS: DNA microarray analysis revealed upregulated expression of many genes and their products including several cytokines and chemokines, as well as the inflammatory marker, lipocalin 2 gene. The gene expression and protein upregulation of lipocalin 2 were synergistically affected by endotoxin and tumor necrosis factor (TNF)-α stimulation. In human studies, lipocalin 2 level was significantly associated with creatinine (r = 0.419, P < 0.001) and negatively associated with eGFR (r = -0.365, P < 0.001). Multiple logistic regression analysis revealed a significant association between lipocalin 2 and soluble tumor necrosis factor receptor 2 (sTNF-R2), eGFR and uric acid in general subjects attending regular annual medical check-up (n = 420). When subjects with diabetes were excluded from the analysis, lipocalin 2 remained associated with sTNF-R2, eGFR and uric acid. CONCLUSIONS: Since an activated TNF system, as demonstrated by elevated sTNF-R2, and elevated uric acid were recently implicated in an elevated CKD risk, we conclude that inflammation could play an important role in the pathogenesis of CKD, and that lipocalin 2 is a potential universal marker for impaired kidney function. Furthermore, the results obtained by the current microarray analysis could improve the understanding of gene profiles associated with the pathophysiology of CKD under inflammatory conditions.

Adverse perinatal outcomes related to the delivery mode in women with monochorionic diamniotic twin pregnancies.

AIMS: The association between the planned delivery mode and adverse perinatal outcomes of monochorionic diamniotic (MCDA) twin pregnancies at ≥36 weeks' gestation was evaluated. METHODS: This retrospective cohort study included uncomplicated MCDA twin pregnancies delivered after 36 weeks' gestation during a 10-year period. Cases were classified into the trial of labor (TOL) or cesarean section (CS) group according to the planned delivery mode. The primary outcome was a composite of adverse outcomes for at least one twin, including intrauterine fetal death (IUFD) after 36 weeks, neonatal death, umbilical artery pH<7.1, 5-min Apgar scores<7, hypoxic ischemic encephalopathy (HIE), meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), or acute feto-fetal hemorrhage (AFFH). The relationship between outcomes and the planned delivery mode was evaluated using a multiple logistic regression analysis. RESULTS: We included the 310 pregnancies delivered after 36 weeks' gestation. After excluding 15 patients, the final analysis included 295 MCDA pregnancies: 63% had delivered through TOL and 37% through CS. The incidences of composite adverse outcomes in the TOL and CS groups were 4.3% and 1.9%, respectively. No IUFD, neonatal death, MAS, RDS, or AFFH was observed; two infants in each group developed HIE. Adverse outcomes were not significantly associated with any risk factor, including delivery through TOL. CONCLUSION: TOL may not influence the perinatal outcomes of MCDA twin pregnancies delivered at ≥36 weeks' gestation.

Luteolin Is a Potential Immunomodulating Natural Compound against Pulpal Inflammation.

Aim: The present study evaluated the therapeutic effects of luteolin in alleviating pulpitis of dental pulp- (DP-) derived microvesicles (MVs) via the inhibition of protein kinase R- (PKR-) mediated inflammation. Methodology. Proteomic analysis of immortalized human dental pulp (DP-1) cell-derived MVs was performed to identify PKR-associated molecules. The effect of luteolin on PKR phosphorylation in DP-1 cells and the expression of tumor necrosis factor-α (TNF-α) in THP-1 macrophage-like cells were validated. The effect of luteolin on cell proliferation was compared with that of chemical PKR inhibitors (C16 and 2-AP) and the unique commercially available sedative guaiacol-parachlorophenol. In the dog experimental pulpitis model, the pulps were treated with (1) saline, (2) guaiacol-parachlorophenol, and (3) luteolin. Sixteen teeth from four dogs were extracted, and the pulp tissues were analyzed using hematoxylin and eosin staining. Immunohistochemical staining was performed to analyze the expression of phosphorylated PKR (pPKR), myeloperoxidase (MPO), and CD68. Experimental endodontic-periodontal complex lesions were established in mouse molar through a silk ligature and simultaneous MV injection. MVs were prepared from DP-1 cells with or without pretreatment with 2-AP or luteolin. A three-dimensional microcomputed tomography analysis was performed on day 7 (n = 6). Periodontal bone resorption volumes were calculated for each group (nonligated-ligated), and the ratio of bone volume to tissue volume was measured. Results: Proteomic analysis identified an endogenous PKR activator, and a protein activator of interferon-induced PKR, also known as PACT, was included in MVs. Luteolin inhibited the expressions of pPKR in DP-1 cells and TNF-α in THP-1 cells with the lowest suppression of cell proliferation. In the dog model of experimental pulpitis, luteolin treatment suppressed the expression of pPKR-, MPO-, and CD68-positive cells in pulp tissues, whereas guaiacol-parachlorophenol treatment caused coagulative necrosis and disruption. In a mouse model of endodontic-periodontal complex lesions, luteolin treatment significantly decreased MV-induced alveolar bone resorption. Conclusion: Luteolin is an effective and safe compound that inhibits PKR activation in DP-derived MVs, enabling pulp preservation.

Effect of Periodontal Treatment on Reducing Chronic Inflammation in Systemically Healthy Patients With Periodontal Disease.

BACKGROUND: We determined the effects and an accurate marker of periodontal treatment on serum interleukin (IL)-6 and high-sensitivity C-reactive protein (HsCRP) levels in systemically healthy individuals with periodontal disease. METHODS: This multicenter study included systemically healthy individuals with periodontal disease who received initial periodontal treatment and had no periodontal treatment history. Periodontal parameters, including periodontal inflamed surface area, masticatory efficiency, and periodontal disease classification; serum IL-6 and HsCRP levels; and serum immunoglobulin (Ig)G titers against periodontal pathogens were evaluated at baseline and after treatment. Subjects were classified as low or high responders (group) based on periodontal inflamed surface area changes. RESULTS: There were 153 participants. Only periodontal inflamed surface area changes were markedly different between low and high responders. Periodontal treatment (time point) decreased both serum IL-6 and HsCRP levels. The interaction between group and time point was remarkable only for serum IL-6 levels. Changes in serum immunoglobulin (Ig)G titers against periodontal pathogens were not associated with IL-6 changes in high responders. We analyzed the indirect effect of serum anti-Porphyromonas gingivalis type 2 IgG titer changes using mediation analysis and found no significance. However, the direct effect of group (low or high responder) on IL-6 changes was considerable. CONCLUSIONS: Periodontal treatment effectively decreased serum IL-6 levels, independent of periodontal pathogen infection, in systemically healthy individuals with periodontal disease.

Erratum: Attenuation of postprandial blood glucose in humans consuming isomaltodextrin: carbohydrate loading studies.

[This corrects the article DOI: 10.1080/16546628.2017.1325306.].

The effects of abaloparatide on hip geometry and biomechanical properties in Japanese osteoporotic patients assessed using DXA-based hip structural analysis: results of the Japanese phase 3 ACTIVE-J trial.

Daily subcutaneous injection of 80 µg abaloparatide increased bone mineral density in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. Dual-energy X-ray absorptiometry-based hip structural analysis from ACTIVE-J data showed improved hip geometry and biomechanical properties with abaloparatide compared with placebo. PURPOSE: Abaloparatide (ABL) increased bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. To evaluate the effect of ABL on hip geometry and biomechanical properties, hip structural analysis (HSA) was performed using ACTIVE-J trial data. METHODS: Hip dual-energy X-ray absorptiometry scans from postmenopausal women and men (ABL, n = 128; placebo, n = 65) at baseline and up to week 78 were analyzed to extract bone geometric parameters at the narrow neck (NN), intertrochanteric region (IT), and proximal femoral shaft (FS). Computed tomography (CT)-based BMD and HSA indices were compared between baseline and week 78. RESULTS: ABL treatment showed increased mean percent change from baseline to week 78 in cortical thickness at the NN (5.3%), IT (5.3%), and FS (2.9%); cross-sectional area at the NN (5.0%), IT (5.0%), and FS (2.6%); cross-sectional moment of inertia at the NN (7.6%), IT (5.1%), and FS (2.5%); section modulus at the NN (7.4%), IT (5.4%), and FS (2.4%); and decreased mean percent change in buckling ratio (BR) at the IT (- 5.0%). ABL treatment showed increased mean percent change in total volumetric BMD (vBMD; 2.7%) and trabecular vBMD (3.2%) at the total hip and decreased mean percent change in BR at femoral neck (- 4.1%) at week 78 vs baseline. All the changes noted here were significant vs placebo (P < 0.050 using t-test). CONCLUSION: A 78-week treatment with ABL showed improvement in HSA parameters associated with hip geometry and biomechanical properties vs placebo. TRIAL REGISTRATION: JAPIC CTI-173575.

Epithelial-to-mesenchymal transition, inflammation, subsequent collagen production, and reduced proteinase expression cooperatively contribute to cyclosporin-A-induced gingival overgrowth development.

Drug-induced gingival overgrowth (DIGO), induced by certain immunosuppressive drugs, antihypertensive agents, and antiepileptic drugs, may contribute to the formation of deeper periodontal pockets and intractableness in periodontitis. To date, multiple factors such as enhanced matrix production, inflammation, and reduced matrix degradation might be involved in the pathogenesis of DIGO. We have previously reported that SPOCK-1, a heparan sulfate proteoglycan, could affect gingival thickening by promoting epithelial-to-mesenchymal transition (EMT) in gingival keratinocytes. However, few studies have investigated whether a combination of these factors enhances the DIGO phenotype in animal models. Therefore, we investigated whether SPOCK-1, periodontal inflammation, and cyclosporin-A (CsA) could cooperatively promote gingival overgrowth. We first confirmed that Spock-1 overexpressing (Spock1-Tg) mice showed significantly thicker gingiva and greater alveolar bone loss than WT mice in response to ligature-induced experimental periodontitis. DIGO was induced by the combination of CsA administration and experimental periodontitis was significantly enhanced in Spock1-Tg mice compared to that in WT mice. Ligature-induced alveolar bone loss in CsA-treated Spock1-Tg mice was also significantly greater than that in CsA-treated WT mice, while being accompanied by an increase in Rankl and Col1a1 levels and a reduction in matrix metalloprotease expression. Lastly, SPOCK-1 promoted RANKL-induced osteoclast differentiation in both human peripheral blood mononuclear cells and murine macrophages, while peritoneal macrophages from Spock1-Tg mice showed less TNFα and IL-1ß secretion than WT mice in response to Escherichia coli lipopolysaccharide. These results suggest that EMT, periodontal inflammation, and subsequent enhanced collagen production and reduced proteinase production contribute to CsA-induced DIGO pathogenesis.