Neurotropin® ameliorates chronic pain associated with scar formation in a mouse model: A gene expression analysis of the inflammatory response.

Background: Scar formation after trauma and surgery involves an inflammatory response and can lead to the development of chronic pain. Neurotropin® (NTP) is a nonprotein extract of inflamed skin of rabbits inoculated with vaccinia virus. It has been widely used for the treatment of chronic pain. However, the in vivo effects of NTP on painful scar formation have not been determined. To investigate the molecular mechanisms underlying the effects of NTP on the inflammatory response, we evaluated gene expression in the scar tissues and dorsal root ganglions (DRGs) of mice administered NTP and control mice. Methods and results: Mice injected with saline or NTP were used as controls; other mice were subjected to surgery on the left hind paw to induce painful scar formation, and then injected with saline or NTP. Hind paw pain was evaluated by measuring the threshold for mechanical stimulation using the von Frey test. The paw withdrawal threshold gradually returned to pre-operative levels over 4 weeks post-operation; NTP-treated mice showed a significantly shortened recovery time of approximately 3 weeks, suggesting that NTP exerted an analgesic effect in this mouse model. Total RNA was extracted from the scarred hind paw tissues and DRGs were collected 1 week post-operation for a microarray analysis. Gene set enrichment analysis revealed that the expression of some gene sets related to inflammatory responses was activated or inhibited following surgery and NTP administration. Quantitative real-time reverse transcription-polymerase chain reaction analysis results for several genes were consistent with the microarray results. Conclusion: The administration of NTP to the hind paws of mice with painful scar formation following surgery diminished nociceptive pain and reduced the inflammatory response. NTP inhibited the expression of some genes involved in the response to surgery-induced inflammation. Therefore, NTP is a potential therapeutic option for painful scar associated with chronic pain.

Chiral Supramolecular Organogel Constructed Using Riboflavin and Melamine: Its Application in Photo-Catalyzed Colorimetric Chiral Sensing and Enantioselective Adsorption.

The synthesis of a chiral supramolecular organogel via the hierarchical helical self-assembly of optically active riboflavin and melamine derivatives is described herein. Owing to the photocatalysis of riboflavin and the supramolecular chirality induced in the helically stacked riboflavin/melamine complex, the gel is observed to act as a light-stimulated chiral sensor of optically active alcohols by detecting the change in color from yellow to green. The gel also served as an efficient chiral adsorbent, enabling optical resolution of a racemic compound with high chiral recognition ability.

Aerobic oxidative synthesis of benzimidazoles by flavin photocatalysis.

Flavin photocatalysis were utilised for an aerobic oxidative reaction between arylamines and o-phenylenediamine. This metal-free reaction proceeded in methanol under visible light irradiation and consumed only atmospheric molecular oxygen, providing a novel eco-friendly method for the synthesis of benzimidazoles.

Oncostatin M suppresses bone morphogenetic protein-4-induced osteoprotegerin synthesis in MC3T3-E1 osteoblast-like cells: p70 S6 kinase attenuation.

Evidence is accumulating that osteal macrophages, in addition to bone-resorbing osteoclasts and bone-forming osteoblasts, participate vitally in bone remodeling process. Oncostatin M (OSM), an inflammatory cytokine belonging to interleukin-6 superfamily, is recognized as an essential factor secreted by osteal macrophages to orchestrate bone remodeling. Osteoprotegerin (OPG) produced by osteoblasts regulates osteoclastogenesis. We have reported that bone morphogenetic protein-4 (BMP-4) stimulates OPG synthesis in MC3T3-E1 osteoblast-like cells, and that SMAD1/5/8(9), p38 mitogen-activated protein kinase (MAPK), and p70 S6 kinase are involved in the OPG synthesis. The present study aims to investigate the effect of OSM on the synthesis of OPG stimulated by BMP-4 in osteoblasts. OSM suppressed the release and the mRNA expression of OPG upregulated by BMP-4 in MC3T3-E1 cells. Neither the BMP-4-induced phosphorylation of SMAD1/5/9 nor that of p38 MAPK was affected by OSM. On the other hand, the phosphorylation of p70 S6 kinase stimulated by BMP-4 was considerably suppressed by OSM. These results strongly suggest that OSM suppresses the BMP-4-stimulated OPG synthesis via inhibition of the p70 S6 kinase-mediated pathway in osteoblast-like cells.

What Are the Sex-Based Differences of Acetabular Coverage Features in Hip Dysplasia?

BACKGROUND: Eccentric rotational acetabular osteotomy is performed to prevent osteoarthritis caused by developmental dysplasia of the hip (DDH). To achieve sufficient acetabular coverage, understanding the characteristics of acetabular coverage in DDH is necessary. However, the features of acetabular coverage in males with DDH remain unclear. We thought that the differences in acetabular coverage between females and males might be associated with the differences in pelvic morphology between the sexes. QUESTIONS/PURPOSES: (1) What are the differences in the acetabular coverage between females and males with DDH? (2) What are the differences in the rotations of the ilium and ischium between females and males with DDH? (3) What is the relationship between the rotation of the ilium and ischium and the acetabular coverage at each height in females and males with DDH? METHODS: Between 2016 and 2023, 114 patients (138 hips) underwent eccentric rotational acetabular osteotomy at our hospital. We excluded patients with Tönnis Grade 2 or higher, a lateral center-edge angle of 25º or more, and deformities of the pelvis or femur, resulting in 100 patients (122 hips) being included. For female patients (98 hips), the median (range) age was 40 years (10 to 58), and for the male patients (24 hips), it was 31 years (14 to 53). We used all patients' preoperative AP radiographs and CT data. The crossover sign, posterior wall sign, and pelvic width index were evaluated in AP radiographs. The rotation of the innominate bone in the axial plane was evaluated at two different heights, specifically at the slice passing through the anterior superior iliac spine and the slice through the pubic symphysis and ischial spine in CT data. Furthermore, we evaluated the anterior and posterior acetabular sector angles. Comparisons of variables related to innominate bone measurements and acetabular coverage measurements between females and males in each patient were performed. The correlations between pelvic morphology measurements and acetabular coverage were evaluated separately for females and males, and the results were subsequently compared to identify any sex-specific differences. For continuous variables, we used the Student t-test; for binary variables, we used the Fisher exact test. A p value less than 0.05 was considered statistically significant. RESULTS: In the evaluation of AP radiographs, an indicator of acetabular retroversion-the crossover sign-showed no differences between the sexes, whereas the posterior wall sign (females 46% [45 of 98] hips versus males 75% [18 of 24] hips, OR 3.50 [95% confidence interval (CI) 1.20 to 11.71]; p = 0.01) and pelvic width index less than 56% (females 1% [1 of 98] versus males 17% [4 of 24], OR 18.71 [95% CI 1.74 to 958.90]; p = 0.005) occurred more frequently in males than in females. There were no differences in the iliac rotation parameters, but the ischium showed more external rotation in males (females 30° ± 2° versus males 24° ± 1°; p < 0.001). Regarding acetabular coverage, no differences between females and males were observed in the anterior acetabular sector angles. In contrast, males showed smaller values than females for the posterior acetabular sector angles (85° ± 9° versus 91° ± 7°; p = 0.002). In females, a correlation was observed between iliac rotation and acetabular sector angles (anterior acetabular sector angles: r = -0.35 [95% CI -0.05 to 0.16]; p < 0.001, posterior acetabular sector angles: r = 0.42 [95% CI 0.24 to 0.57]; p < 0.001). Similarly, ischial rotation showed a correlation with both acetabular sector angles (anterior acetabular sector angles: r = -0.34 [95% CI -0.51 to -0.15]; p < 0.001 and posterior acetabular sector angles: r = 0.45 [95% CI 0.27 to 0.59]; p < 0.001). Thus, in females, we observed that external iliac rotation and ischial internal rotation correlated with increased anterior acetabular coverage and reduced posterior coverage. In contrast, although acetabular coverage in males showed a correlation with iliac rotation (anterior acetabular sector angles: r = -0.55 [95% CI -0.78 to -0.18]; p = 0.006 and posterior acetabular sector angles: r = 0.74 [95% CI 0.48 to 0.88]; p < 0.001), no correlation was observed with ischial rotation. CONCLUSION: In males, acetabular retroversion occurs more commonly than in females and is attributed to their reduced posterior acetabular coverage. In females, an increase in the posterior acetabular coverage was correlated with the external rotation angle of the ischium, whereas in males, no correlation was found between ischial rotation and posterior acetabular coverage. In treating males with DDH via eccentric rotational acetabular osteotomy, it is essential to adjust bone fragments to prevent inadequate posterior acetabular coverage. Future studies might need to investigate the differences in acetabular coverage between males and females in various limb positions and consider the direction of bone fragment rotation. CLINICAL RELEVANCE: Our findings suggest that males with DDH exhibit acetabular retroversion more frequently than females, which is attributed to the reduced posterior acetabular coverage observed in males. The smaller posterior acetabular coverage in males might be related to differences in ischial morphology between sexes. During eccentric rotational acetabular osteotomy for males with DDH, adequately rotating acetabular bone fragments might be beneficial to compensate for deficient posterior acetabular coverage.

Extension of the Antero-Posterior Necrotic Regions Associated With Collapse Cessation in Osteonecrosis of the Femoral Head.

BACKGROUND: Collapse cessation is of utmost importance following a long period of collapse due to osteonecrosis of the femoral head (ONFH). This study investigated the relationship between collapse cessation and the extent of the necrotic regions of ONFH. METHODS: Overall, 74 patients who had symptomatic ONFH (collapse < 3 mm) at the first visit with a minimum follow-up of 3 years were included in this study. Patients were categorized based on collapse progression or cessation into the progression and stable groups. The extent of the antero-posterior (AP) and medio-lateral necrotic regions between the groups was assessed using sagittal and coronal sections of T1-magnetic resonance imaging. Additionally, the most effective cutoff value was determined from the receiving operating characteristic curve where collapse cessation could be obtained, while the survival rates were determined with collapse progression as the endpoints were evaluated. RESULTS: Overall, 45 and 29 patients were in the progression and stable groups, respectively. The AP and medio-lateral necrotic regions were significantly different (P < .01 and P < .01, respectively) between the progression and stable groups. A cutoff value of 62.1% of the AP necrotic regions was determined from the receiving operating characteristic curve analysis. The 5-year survival rates with collapse progression as the endpoints were 5.4 and 77.8% in the AP necrotic regions of ≥62.1 and <62.1%, respectively (P < .01). CONCLUSIONS: Cases with AP necrotic regions of ≤62.1% can be expected to have collapse cessation, which could be a useful index for ONFH treatment strategies. LEVEL OF EVIDENCE: Level IV.

Risk factors for intraoperative femoral fractures in cementless bipolar hip arthroplasty for femoral neck fracture in multicenter: The TRON group study.

BACKGROUND: Intraoperative femoral fractures are more common in cementless bipolar hip arthroplasty (BHA) for displaced femoral neck fractures than they are in cemented BHA and remain one of the major concerns. This study aimed to investigate the risk factors for intraoperative femoral fractures in cementless BHA. METHODS: The study included 1,392 patients who underwent cementless BHA for displaced femoral neck fractures from January 2015 to December 2019 in 14 hospitals of the Trauma Research Group. They were divided into two groups according to the presence or absence of intraoperative femoral fractures, and factors associated with intraoperative fractures were statistically examined. RESULTS: Forty (2.9 %) intraoperative and 28 (2.0 %) postoperative, totally 68 (4.9 %) femoral fractures occurred. The mean age of the patients, presence of opposite-side proximal femoral fracture, approach, and cementless stem design were significantly different between the two groups (P < 0.05). The logistic regression analysis model showed that a fully HA-coated stem (odds ratio, 4.12; 95 % confidence interval, 1.43-11.9) was an independent factor associated with intraoperative femoral fractures. CONCLUSION: This study investigated the risk factors associated with intraoperative fractures and showed that fully HA-coated stems were an independent factor associated with intraoperative femoral fractures. Surgeons should be cautious in the early stages of introducing fully HA-coated stems.

A large preoperative pelvic oblique angle affects perception of leg length discrepancy after total hip arthroplasty.

BACKGROUND: In some cases, patients feel a perceived leg length discrepancy (P-LLD) despite no radiographic leg length discrepancy (R-LLD) after total hip arthroplasty (THA). We aimed to investigate the rate of postoperative P-LLD and the factors that cause postoperative P-LLD. METHODS: A retrospective study was conducted on 100 patients with R-LLD ≤5 mm after THA. Patients were classified into two groups based on P-LLD post-THA: group P (with P-LLD) and group E (without P-LLD). Relevant data on the general characteristics and radiological findings between the two groups were compared. RESULTS: We observed that 25 & 75% of patients belonged to group P and group E, respectively, with no significant difference in patient background. Postoperative Japanese Orthopedic Association (JOA) classification of pain and activities of daily living scores were significantly lower in group P than in group E (37.2 ± 3.9 vs. 39.1 ± 2.2, respectively; P = 0.013, and 16.2 ± 4.2 vs. 18.2 ± 2.2, respectively; P = 0.011). The preoperative pelvic oblique angle (POA) was significantly larger in group P than in group E (3.3 ± 2.3° vs. -0.2 ± 2.1°; respectively; P < 0.01). The pelvis tilted toward the surgical side was significantly higher in group P than in group E(88% vs 57%; respectively; P = 0.013). The preoperative C7 coronal vertical axis (C7 CVA) was significantly larger in group P than in group E (6.7 ± 14.7 mm vs. -0.2 ± 10.3 mm; respectively; P = 0.028). Multivariate logistic analysis revealed that preoperative POA (OR, 3.71; 95% CI: 1.86-8.12; P < 0.01) and the pelvis tilted toward the surgical side (OR, 4.14; 95% CI: 2.07-9.71; P = 0.022) were independent risk factors for P-LLD after THA. CONCLUSION: Even though there was no postoperative R-LLD, 25% of patients had P-LLD. A large preoperative POA and the pelvis tilted toward the surgical side were independent risk factors for P-LLD after THA.

Fall risk in patient with dysplastic hip osteoarthritis.

PURPOSE: Patients with dysplastic hip osteo arthritis (DHOA) often have a spinopelvic imbalance, and they are more likely to experience falls. This study aimed to evaluate the risk factors for falls in patients with DHOA, including spinopelvic parameters. METHODS: In this cross-sectional study, a total of 103 patients with DHOA were included from 2019 to 2021. Fall risk was evaluated using the Fall Risk Index 5 items version (FRI-5). Demographics, functional outcomes, and spinopelvic parameters were compared between the high-risk group (FRI-5 ≥ 6) and the low-risk group (FRI-5 < 6). Multivariate analysis was performed using factors with significant differences in univariate analysis. RESULTS: High-risk and low-risk groups comprised 54 and 49 patients, respectively. Females were significantly more common in the high-risk group than in the low-risk group. The Harris Hip Score was significantly lower in the high-risk group than in the low-risk group (p = 0.02). Pelvic incidence, tilt, and obliquity were significantly higher in the high-risk group than in the low-risk group (p < 0.01). In multivariate analysis, female sex (odds ratio [OR]: 3.76, 95% confidence interval [CI]: 1.11-12.64, p = 0.03), pelvic obliquity (OR: 1.36, 95% CI: 1.09-1.71, p < 0.01), and Harris hip score (OR: 0.96, 95% CI: 0.93-0.99, p = 0.02) were identified as risk factors. CONCLUSION: Female sex, pelvic obliquity, and low Harris hip score were associated with an increased risk of falls among patients with DHOA.

Association of mid-thigh quadriceps muscle quality with postoperative outcomes in patients with hip osteoarthritis undergoing total hip arthroplasty: a retrospective cohort study.

PURPOSE: Muscle quality is more important than muscle mass for assessing physical function. Computed tomography (CT) is used to evaluate intramuscular fatty infiltration. The mid-thigh quadriceps CT attenuation values (CTV) expressed in Hounsfield units (HU) negatively correlate with physical function. Patients with hip osteoarthritis (HOA) have lower extremity muscle atrophy, including decreased cross-sectional area (CSA), CTV, and muscle strength. Using preoperative CT images, we investigated the association between mid-thigh quadriceps CSA, CTV, and postoperative outcomes in patients with HOA. METHODS: This study included 62 patients who had unilateral HOA (62 hips) and underwent total hip arthroplasty (THA). We investigated the association between preoperative and postoperative Japanese Orthopaedic Association (JOA) hip scores, 12-item Short Form survey (SF-12), mid-thigh quadriceps CSA, and CTV. RESULTS: The mean age was 64.7 ± 10.1 years, with 15 men (24.2%), and the mean body mass index was 24.3 ± 4.3 kg/m2. Secondary HOA was present in 79.0% of patients. The mean CSA and CTV of the mid-thigh quadriceps on the operative side were 38.8 ± 9.8 cm2 and 40.3 ± 7.8 HU, respectively. Multiple regression analyses adjusted for age and sex showed that preoperative mid-thigh quadriceps CSA was not associated with preoperative and postoperative JOA hip scores or SF-12. The preoperative mid-thigh quadriceps CTV was associated with the postoperative JOA hip score in the gait ability domain and SF-12 in the physical component summary domain. CONCLUSION: Preoperative muscle quality is associated with postoperative outcomes in patients who have HOA regardless of age and sex.

Atom-Economical Syntheses of Dihydropyrroles Using Flavin-Iodine-Catalyzed Aerobic Multistep and Multicomponent Reactions.

Herein, we report facile, atom-economical syntheses of multisubstituted 2,3-dihydropyrroles using flavin-iodine-catalyzed aerobic oxidative multistep transformations of chalcones with ß-enamine ketones or 1,3-dicarbonyl compounds and amines. Exploiting coupled flavin-iodine catalysis, the multistep reaction, including C-C and C-N bond formation, is promoted only by the consumption of O2 (1 atm), thus allowing aerobic oxidative synthesis that generates green H2O as the only waste.

Aerobic cross-dehydrogenative coupling of toluenes and o-phenylenediamines by flavin photocatalysis for the facile synthesis of benzimidazoles.

Herein, we demonstrate a green atom-economical synthesis of benzimidazoles via the flavin-photocatalysed aerobic oxidative cross-dehydrogenative coupling of toluenes and o-phenylenediamines. The proposed metal-free reaction proceeds in methanol/H2O under visible light irradiation by consuming only molecular oxygen from atmospheric air and produces only water as waste.

Resveratrol inhibits basic fibroblast growth factor-induced macrophage colony-stimulating factor synthesis via the PI3-kinase/Akt pathway in osteoblasts.

Resveratrol is a natural polyphenol found in grapes and beneficial for human health. Resveratrol regulates basic fibroblast growth factor (bFGF)-induced osteoprotegerin synthesis through Akt pathway in osteoblast-like MC3T3-E1 cells. In this study, we investigated resveratrol effects on bFGF-induced macrophage colony-stimulating factor (M-CSF) synthesis in MC3T3-E1 cells. bFGF significantly stimulated release and mRNA expression of M-CSF, which was reduced by resveratrol and SRT1720, sirtuin 1 (SIRT1) activator. Inauhzin, SIRT1 inhibitor, reversed inhibitory effects of resveratrol on bFGF-induced mRNA expression of M-CSF. Deguelin, Akt inhibitor, and LY294002, phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, reduced bFGF-induced M-CSF synthesis. Inauhzin reversed inhibitory effects of resveratrol on bFGF-induced Akt phosphorylation. Suppressive effect of resveratrol on bFGF-induced osteoprotegerin mRNA expression was confirmed in the identical samples using in experiment of M-CSF mRNA expression. Therefore, resveratrol reduces bFGF-induced M-CSF synthesis in addition to osteoprotegerin synthesis by inhibiting PI3-kinase/Akt pathway and suppressive effects are mediated through SIRT1 activation in osteoblasts.

Risk factors for lateralization or superiorization of the center of the femoral head in eccentric rotational acetabular osteotomy.

PURPOSE: This study aimed to clarify the factors that cause the lateralization and superiorization of the femoral head after eccentric rotational acetabular osteotomy (ERAO) by examining the three-dimensional morphology of the osteotomy site using computed tomography (CT). METHODS: This study included 52 patients who underwent ERAO for hip dysplasia. Postoperatively, the center of the femoral head was measured for lateralization and superiorization. We defined the iliac and sciatic osteotomy angles in the coronal and axial CT planes, respectively. The surgical factors for lateralization and superiorization were analysed using multiple logistic regression analysis. We also analysed the relationship between the femoral head relocation and clinical outcomes (as assessed using Japanese Orthopaedic Association (JOA) scores). RESULTS: Thirty-five patients had hips with lateralized femoral heads, and 25 patients' femoral heads were superiorized. Logistic regression analysis revealed that a higher osteotomy angle of the ilium in the coronal plane served as a significant predictor of superiorization of the femoral head. Similarly, a larger osteotomy angle of the ischium in the axial plane and the amount of change in the lateral centre edge angle were identified as predictors of lateralization. A weak negative correlation was observed between the amount of lateralization and the JOA score. CONCLUSION: Large osteotomy angles in the superior and posterior aspects of the acetabulum carry a risk of superiorization and lateralization of the center of the femoral head. Surgeons should be aware of the need to chisel through the internal plate to achieve the results described in the ERAO theory. STUDY DESIGN: A single-center, retrospective study.

Hip function in patients undergoing conservative treatment for osteonecrosis of the femoral head.

PURPOSE: Once collapsed, osteonecrosis of the femoral head (ONFH) generally obtains collapse cessation naturally and surgical intervention can be avoided in the long term. This study aimed to investigate the process of hip function and secondary osteoarthritis changes in ONFH patients undergoing conservative treatment. METHODS: We included 54 patients with symptomatic ONFH at the first visit with a minimum follow-up of three years with conservative treatment. Patients were divided into two groups based on collapse cessation < 3 mm (stable group) or progression to > 3 mm (progression group). Additionally, we investigated age, sex, body mass index (BMI), etiology, contralateral side hip joint, the Japanese Investigation Committee (JIC) type classification, Harris hip score (HHS), Japanese Orthopaedic Association Hip-Disease Evaluation Questionnaire (JHEQ), and survival rate with secondary osteoarthritis as the endpoint. RESULTS: The stable and progression groups had 31 and 23 patients, respectively. No significant differences in age, sex, BMI, and aetiology were observed between the two groups, except for the contralateral side hip joint and JIC type classification. The HHS and JHEQ were significantly improved at the final follow-up than at the first visit in the stable group. However, there were no significant differences in HHS and JHEQ at the final follow-up than at the first visit in the progression group. The five year survival rates with secondary osteoarthritis as the endpoint were significantly higher in the stable group (100%) than in the progression group (32.5%). CONCLUSION: Hip joint function improved by continuing conservative treatment in ONFH patients with collapse cessation < 3 mm.

Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac.

CXCL12, belonging to the CXC chemokine family, is a weak agonist of platelet aggregation. We previously reported that the combination of CXCL12 and collagen at low doses synergistically activates platelets via not CXCR7 but CXCR4, a specific receptor for CXCL12 on the plasma membrane. Recently, we reported that not Rho/Rho kinase, but Rac is involved in the platelet aggregation induced by this combination. Ristocetin is an activator of the von Willebrand factor that interacts with glycoprotein (GP) Ib/IX/V, which generates thromboxane A2 via phospholipase A2 activation, resulting in the release of the soluble CD40 ligand (sCD40L) from human platelets. In the present study, we investigated the effects of a combination of ristocetin and CXCL12 at low doses on human platelet activation and its underlying mechanisms. Simultaneous stimulation with ristocetin and CXCL12 at subthreshold doses synergistically induce platelet aggregation. A monoclonal antibody against not CXCR7 but CXCR4 suppressed platelet aggregation induced by the combination of ristocetin and CXCL12 at low doses. This combination induces a transient increase in the levels of both GTP-binding Rho and Rac, followed by an increase in phosphorylated cofilin. The ristocetin and CXCL12-induced platelet aggregation as well as the sCD40L release were remarkably enhanced by Y27362, an inhibitor of Rho-kinase, but reduced by NSC23766, an inhibitor of the Rac-guanine nucleotide exchange factor interaction. These results strongly suggest that the combination of ristocetin and CXCL12 at low doses synergistically induces human platelet activation via Rac and that this activation is negatively regulated by the simultaneous activation of Rho/Rho-kinase.

Bisphosphonate treatment is associated with decreased mortality rates in patients after osteoporotic vertebral fracture.

The aim of this study is to investigate the effect of bisphosphonate (BP) on mortality after osteoporotic vertebral fracture (OVF). BP medication (hazard ratios = 0.593; 95%CI: 0.361-0.976) was significantly associated with reduced all-cause mortality after OVF. PURPOSE: Osteoporotic vertebral fracture (OVF) is the most common type of fragility fracture. Bisphosphonate (BP) medication was suggested to have positive effects on both fracture prevention and recovery outcomes. The aim of this study is to investigate the effect of BP on mortality after OVF. METHODS: This cohort study involved 535 patients (170 males and 365 females), aged ≥ 65 years (mean age: 82.6 ± 7.0 years, mean follow-up periods: 33.0 ± 25.8 months) who were hospitalized after OVF from January 2011 to December 2019 at a public hospital. Patients treated with PTH (parathyroid hormone), PTH or PTHrp analogues, denosumab, and selective estrogen receptor modulators were excluded. Kaplan-Meier survival curves on mortality of patients with OVF with and without BP treatment were prepared, and log-rank tests were performed. Cox proportional hazards model was used to identify factors associated with mortality after OVF. RESULTS: This study included 163 (30.5%) patients treated with BP. Kaplan-Meier survival curves showed that the mortality rate after OVF was significantly lower in patients treated with BP (P < 0.001). Cox proportional hazards model showed that older age (hazard ratios [HR] = 1.066; 95%CI:1.035-1.103), male sex (HR = 2.248; 95%CI:1.427-3.542), malnutrition (geriatric nutritional risk index < 92) (HR = 1.691; 95%CI:1.005-2.846), BP medication (HR = 0.593; 95%CI: 0.361-0.976), and Japanese Orthopaedic Association score at discharge (HR = 0.941; 95%CI: 0.892-0.993) were significantly associated with all-cause mortality after OVF. CONCLUSIONS: BP medication is beneficial not only for fracture prevention but also for mortality after OVF.

Incretins Enhance PGF2α-Induced Synthesis of IL-6 and Osteoprotegerin in Osteoblasts.

Incretins including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are secreted from the small intestine after oral food ingestion, are currently well-known to stimulate insulin secretion from pancreatic ß-cells and used for the treatment of type 2 diabetes mellitus. We have previously reported that prostaglandin F2α (PGF2α) stimulates the synthesis of interleukin-6 (IL-6) and osteoprotegerin in osteoblast-like MC3T3-E1 cells, and that IL-6 and osteoprotegerin release are mediated through the p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways. In the present study, we investigated the effects of incretins including GLP-1 and GIP, on the PGF2α-induced synthesis of IL-6 and osteoprotegerin and examined the detailed mechanism in osteoblast-like MC3T3-E1 cells. We found that GIP and GLP-1 significantly stimulated the PGF2α-induced synthesis of IL-6 in osteoblast-like MC3T3-E1 cells. In addition, GIP and GLP-1 significantly enhanced the PGF2α-induced mRNA expression levels of IL-6. On the other hand, GIP and GLP-1 markedly stimulated the PGF2α-induced synthesis of osteoprotegerin. However, the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase, or JNK induced by PGF2α was not affected by GIP or GLP-1. Therefore, these results strongly suggest that incretins enhance the PGF2α-induced synthesis of IL-6 and osteoprotegerin in osteoblast-like MC3T3-E1 cells. However, these syntheses are not mediated through p44/p42 MAP kinase, p38 MAP kinase, or JNK pathways.

Attenuation by HSP90 inhibitors of EGF-elicited migration of osteoblasts: involvement of p44/p42 MAP kinase.

BACKGROUND: We have demonstrated that epidermal growth factor (EGF)-induced migration of osteoblast-like MC3T3-E1 cells is mediated through p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase, stress-activated protein kinase/ c-Jun N-terminal kinase (SAPK/JNK), and Akt.The molecular chaperone heat shock protein 90 (HSP90) is abundantly expressed in osteoblasts. However, the role of HSP90 in osteoblast migration remains obscure. OBJECTIVE: In this study, we investigated the effect of HSP90 inhibitors on the EGF-induced migration of MC3T3-E1 cells and the mechanism. METHODS: Clonal osteoblast-like MC3T3-E1 cells were treated with the HSP90 inhibitors geldanamycin or onalespib and then stimulated with EGF. Cell migration was evaluated using the transwell cell migration assay and wound-healing assay. The viability of MC3T3-E1 cells was analyzed using the Cell Counting Kit-8. The phosphorylation of p44/p42 MAP kinase, p38 MAP kinase, SAPK/JNK, Akt, and protein kinase-like endoplasmic reticulum kinase (PERK) was evaluated by western blot analysis. RESULTS: EGF-induced migration was significantly suppressed by geldanamycin and onalespib, evaluated by both transwell cell migration assay and wound-healing assay. Geldanamycin and onalespib did not significantly alter cell viability. Geldanamycin and onalespib markedly reduced the EGF-induced phosphorylation of p44/p42 MAP kinase, but not p38 MAP kinase or Akt. By contrast, geldanamycin and onalespib increased the EGF-induced phosphorylation of SAPK/JNK. PERK phosphorylation was not significantly affected by geldanamycin or onalespib. CONCLUSION: Our results strongly suggest that HSP90 inhibitors reduce the EGF-induced osteoblast migration through the p44/p42 MAP kinase.

Metal-Free Atom-Economical Synthesis of Tetra-Substituted Imidazoles via Flavin-Iodine Catalyzed Aerobic Cross-Dehydrogenative Coupling of Amidines and Chalcones.

Herein, we demonstrated the oxidative cross-dehydrogenative coupling between amidines and chalcones catalyzed by flavin and iodine. The riboflavin-iodine catalytic system played multiple roles in substrate- and O2-activation, enabling the facile and atom-economical synthesis of tetra-substituted imidazoles in good yields (60-87%). This metal-free reaction consumed only 1 equiv of molecular oxygen and generated 2 equiv of environmentally benign H2O as the only byproduct.