Ribosomal protein S3 associates with the TFIIH complex and positively regulates nucleotide excision repair.

In mammalian cells, the bulky DNA adducts caused by ultraviolet radiation are mainly repaired via the nucleotide excision repair (NER) pathway; some defects in this pathway lead to a genetic disorder known as xeroderma pigmentosum (XP). Ribosomal protein S3 (rpS3), a constituent of the 40S ribosomal subunit, is a multi-functional protein with various extra-ribosomal functions, including a role in the cellular stress response and DNA repair-related activities. We report that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. For optimal repair of UV-induced duplex DNA lesions, the strong helicase activity of the TFIIH complex is required for unwinding damaged DNA around the lesion. Here, we show that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV radiation through XPD and rpS3 interaction. Additionally, the knockdown of rpS3 caused reduced NER efficiency in HeLa cells and the overexpression of rpS3 partially restored helicase activity of the TFIIH complex of XP-D cells in vitro. We also present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We propose that rpS3 is an accessory protein of the NER pathway and its recruitment to the repair machinery augments repair efficiency upon UV damage by enhancing XPD helicase function and increasing its turnover rate.

Severe Periodontal Disease Increases Acute Myocardial Infarction and Stroke: A 10-Year Retrospective Follow-up Study.

This study aimed to evaluate the causal association of periodontal disease with acute myocardial infarction (AMI) and stroke, after controlling for various confounders among the Korean population. A retrospective cohort study using the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) was performed during 2002 to 2015 (baseline: 2002 to 2005; follow-up: 2006 to 2015) in the Republic of Korea. A total of 298,128 participants with no history of AMI or stroke were followed up for 10 y. AMI and stroke were defined by a diagnosis using the International Classification of Diseases, 10th Revision (ICD-10) guideline. Periodontal condition was classified into 3 groups (healthy, moderate periodontal disease, severe periodontal disease [SPD]) using the combination of ICD codes, treatment codes in the NHIS, and recommendation of periodontal treatment by the dentists in HEALS. Various confounders, such as sociodemographic, behavioral, systemic, and oral health factors, including hypercholesterolemia, were considered. Multivariable Cox regression analysis was applied to estimate adjusted incidence rate ratio (adjusted hazard ratio [aHR]) based on person-year of periodontal condition for AMI, stroke, and nonfatal major adverse cardiovascular events (MACEs) encompassing AMI or stroke controlling for various confounders. Stratified analyses according to age group, sex, and toothbrushing frequency were also performed. After controlling for various confounders, participants with SPD compared with non-SPD participants had a higher incidence by 11% for AMI (aHR, 1.11; 95% confidence interval [CI], 1.02-1.20), by 3.5% for stroke (aHR, 1.035; 95% CI, 1.01-1.07), and by 4.1% for MACEs (aHR, 1.04; 95% CI, 1.01-1.07). The association of SPD with AMI and MACE was highly modified in females and adults aged 40 to 59 y. In the total Korean population, SPD increased total AMI events by 4.3%, total stroke events by 1.4%, and the total MACEs by 1.6%. Our data confirmed that SPD was causally associated with the new events of AMI and stroke.

A Case-Control Study of Fluoridation and Osteosarcoma.

Public health policy decisions in the United States have resulted in 62.4% of the population having access to fluoridated water. The purpose of this study was to examine the association between community water fluoridation and osteosarcoma. A secondary data analysis was performed with data collected from 2 separate but linked studies. Patients for phase 1 and phase 2 were selected from US hospitals via a matched case-control study design. For both phases, cases included patients diagnosed with osteosarcoma, and controls were patients diagnosed with other bone tumors or nonneoplastic conditions. In phase 1, cases (n = 209) and controls (n = 440) were patients of record in the participating orthopedic departments from 1989 to 1993. In phase 2, cases (n = 108) and controls (n = 296) were incident patients who were identified and treated by orthopedic physicians from 1994 to 2000. This analysis included all patients who met eligibility criteria on whom we had complete data on covariates, exposures, and outcome. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the association of community water fluoridation with osteosarcoma. A modestly significant interaction existed between fluoridation living status and bottled water use (P = 0.047). The adjusted OR for osteosarcoma and ever having lived in a fluoridated area for nonbottled water drinkers was 0.51 (95% CI, 0.31 to 0.84; P = 0.008). In the same comparison, the adjusted OR for bottled water drinkers was 1.86 (95% CI, 0.54 to 6.41; P = 0.326). Findings from this study demonstrated that community water fluoridation is not associated with an increased risk for osteosarcoma.

Association of Periodontitis with Oral Cancer: A Case-Control Study.

The association between oral squamous cell carcinoma (OSCC) and periodontitis in large hospital cases with cohort controls has yet to be evaluated. The aim of this study was to investigate the association of periodontitis with OSCC across tumor location and tumor-node-metastasis (TNM) stage among Koreans ( N = 424). OSCC cases ( n = 146) were recruited from Seoul National University Dental Hospital and matched by age, sex, and smoking to controls ( n = 278) from the Yangpyeong health and periodontal cohort in Korea. OSCC was diagnosed through biopsy and radiographs, including computed tomography and magnetic resonance imaging. Tumor location and TNM stage were classified after the surgery. Periodontitis was defined by alveolar bone loss with panoramic radiographs following the guidelines of the Fifth European Workshop in Periodontology. Alcohol intake, education, physical activity, obesity by body mass index, hypertension by blood pressure, diabetes by plasma glucose, and hypercholesterolemia by plasma cholesterol were considered as confounders. Information about age, sex, smoking, alcohol intake, education, and physical activity was obtained through interview; body mass index and blood pressure, through physical examination; and preoperative glucose and cholesterol, through laboratory tests. Bivariate analysis was applied with Fisher's exact chi-square test. Multivariable conditional logistic regression models were applied to evaluate the adjusted association of periodontitis with OSCC after controlling for confounders. Subgroup analyses were explored by OSCC and periodontitis. Participants with periodontitis were 3.7 times more likely to have OSCC (adjusted odds ratio [aOR] = 3.66, 95% CI = 1.46 to 9.23) than participants without periodontitis. The differences in periodontitis were not statistically significant across TNM stages of OSCC ( P > 0.05) and its location ( P > 0.05). The link was highlighted among males (aOR = 6.55), elders aged >60 y (aOR = 4.98), and those with more tooth loss (aOR = 9.99). Our data showed that periodontitis was independently associated with OSCC. Thus, the risk of OSCC could be modulated by reducing periodontitis.

Thread lifting: a minimally invasive surgical technique for long-standing facial paralysis.

BACKGROUND: Chronic facial paralysis induces degenerative facial muscle changes on the involved side, thus, making the individual seem as older than their actual age. Furthermore, contralateral facial hypertrophy aggravates facial asymmetry. A thread-lifting procedure has been used widely for correction of a drooping or wrinkled face due to the aging process. In addition, botulinum toxin injection can be used to reduce facial hypertrophy. The aim of study was to evaluate the effectiveness of thread lifting with botulinum toxin injection for chronic facial paralysis. METHODS: A total 34 of patients with chronic facial paralysis were enrolled from March to October 2014. Thread lifting for elevating loose facial muscles on the ipsilateral side and botulinum toxin A for controlling the facial muscle hypertrophy on the contralateral side were conducted. Facial function was evaluated using the Sunnybrook grading system and dynamic facial asymmetry ratios 1 year after treatment. RESULTS: All 34 patients displayed improved facial symmetry and showed improvement in Sunnybrook scores (37.4 vs. 83.3) and dynamic facial asymmetry ratios (0.58 vs 0.92). Of the 34 patients, 28 (82.4%) reported being satisfied with treatment. CONCLUSION: The application of subdermal suspension with a reabsorbable thread in conjunction with botulinum toxin A to optimize facial rejuvenation of the contralateral side constitutes an effective and safe procedure for face lifting and rejuvenation of a drooping face as a result of long-lasting facial paralysis.

Higher risk of hepatocellular carcinoma in chronic hepatitis B vs chronic hepatitis C after achievement of virologic response.

It is unclear whether the achievement of virologic response modifies the risk of hepatocellular carcinoma (HCC) differently in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Our aim was to compare the risk of HCC between patients with CHB and CHC who achieved virological response. We analysed data from patients with CHB treated with entecavir (n=2000) or CHC treated with peg-interferon and ribavirin (n=733) at a tertiary hospital from 2004 to 2011. Virological response was defined as serum HBV DNA<15 IU/mL at 1 year of treatment for CHB or the achievement of sustained virologic response for CHC. Virological response was achieved in 1520 patients with CHB (76.0%) and 475 patients with CHC (64.8%). During the median follow-up period of 6 years, 228 patients with CHB (11.4%) and 59 patients with CHC (8.0%) developed HCC. Among patients with virological response, CHB was independently associated with a significantly higher incidence of HCC (hazard ratio, 2.17; 95% CI, 1.30-3.63; P=.003) than CHC. Among patients without virological response, there were no differences in HCC incidence between the two cohorts (P=.52). In patients with cirrhosis at baseline, the incidence of HCC did not differ between the two cohorts even after achieving virological response (P>.99). In conclusion, patients with CHB treated with entecavir were associated with a higher risk of HCC compared to patients with CHC treated with peg-interferon and ribavirin after achieving virological response. However, the risk of HCC did not differ between the two cohorts if the patients had cirrhosis at baseline, even if virological response was achieved.

Tongue-to-palate resistance training improves tongue strength and oropharyngeal swallowing function in subacute stroke survivors with dysphagia.

Tongue function can affect both the oral and pharyngeal stages of the swallowing process, and proper tongue strength is vital for safe oropharyngeal swallowing. This trial investigated the effect of tongue-to-palate resistance training (TPRT) on tongue strength and oropharyngeal swallowing function in stroke with dysphagia patients. This trial was performed using a 4-week, two-group, pre-post-design. Participants were allocated to the experimental group (n = 18) or the control group (n = 17). The experimental group performed TPRT for 4 weeks (5 days per week) and traditional dysphagia therapy, whereas the control group performed traditional dysphagia therapy on the same schedule. Tongue strength was measured using the Iowa Oral Performance Instrument. Swallowing function was measured using the videofluoroscopic dysphagia scale (VDS) and penetration-aspiration scale (PAS) based on a videofluoroscopic swallowing study. Experimental group showed more improved in the tongue strength (both anterior and posterior regions, P = 0·009, 0·015). In addition, the experimental group showed more improved scores on the oral and pharyngeal phase of VDS (P = 0·029, 0·007), but not on the PAS (P = 0·471), compared with the control group. This study demonstrated the effectiveness of TPRT in increasing tongue muscle strength and improving swallowing function in patients with post-stroke dysphagia. Therefore, we recommend TPRT as an easy and simple rehabilitation strategy for improving swallowing in patients with dysphagia.

Charge-ordering cascade with spin-orbit Mott dimer states in metallic iridium ditelluride.

Spin-orbit coupling results in technologically-crucial phenomena underlying magnetic devices like magnetic memories and energy-efficient motors. In heavy element materials, the strength of spin-orbit coupling becomes large to affect the overall electronic nature and induces novel states such as topological insulators and spin-orbit-integrated Mott states. Here we report an unprecedented charge-ordering cascade in IrTe2 without the loss of metallicity, which involves localized spin-orbit Mott states with diamagnetic Ir(4+)-Ir(4+) dimers. The cascade in cooling, uncompensated in heating, consists of first order-type consecutive transitions from a pure Ir(3+) phase to Ir(3+)-Ir(4+) charge-ordered phases, which originate from Ir 5d to Te 5p charge transfer involving anionic polymeric bond breaking. Considering that the system exhibits superconductivity with suppression of the charge order by doping, analogously to cuprates, these results provide a new electronic paradigm of localized charge-ordered states interacting with itinerant electrons through large spin-orbit coupling.

Importance of charge fluctuations for the topological phase in SmB(6).

Typical Kondo insulators (KIs) can have a nontrivial Z_{2} topology because the energy gap opens at the Fermi energy (E_{F}) by a hybridization between odd- and even-parity bands. SmB_{6} deviates from such KI behavior, and it has been unclear how the insulating phase occurs. Here, we demonstrate that charge fluctuations are the origin of the topological insulating phase in SmB_{6}. Our angle-resolved photoemission spectroscopy results reveal that with decreasing temperature the bottom of the d-f hybridized band at the X[over ¯] point, which is predicted to have odd parity and is required for a topological phase, gradually shifts from below to above E_{F}. We conclude that SmB_{6} is a charge-fluctuating topological insulator.

Massive epistaxis due to pseudoaneurysm of the sphenopalatine artery: a rare post-operative complication of orthognathic surgery.

OBJECTIVE: To introduce pseudoaneurysm of the sphenopalatine artery as the possible aetiology of acute massive epistaxis in patients with a history of orthognathic surgery accompanied by Le Fort I osteotomy. METHODS: Case report and literature review. RESULTS: This paper reports a case of acute life-threatening epistaxis following Le Fort I osteotomy. Computed tomography and angiography showed a pseudoaneurysm of the sphenopalatine artery, which was successfully treated by endovascular embolisation. CONCLUSION: Although a pseudoaneurysm of the sphenopalatine artery following Le Fort I osteotomy is extremely rare, it should be considered as the possible aetiology of acute massive epistaxis in patients with a history of orthognathic surgery accompanied by Le Fort I osteotomy.

Fusobacterium nucleatum GroEL induces risk factors of atherosclerosis in human microvascular endothelial cells and ApoE(-/-) mice.

Infection and inflammation are risk factors in the initiation and progression of atherosclerosis. Periodontitis is one of the most prevalent chronic inflammations of the oral cavity, and has been reported to be associated with systemic disease. In this study, we evaluated whether the heat-shock protein GroEL of Fusobacterium nucleatum, one of the most prevalent bacteria in periodontitis, induces factors that predispose to atherosclerosis in human microvascular endothelial cells (HMEC-1) and apolipoprotein E-deficient (ApoE(-/-)) mice. GroEL induced the expression of chemokines such as monocyte chemoattractant protein-1 and interleukin-8 as well as cell adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. GroEL induced the activity of tissue factor and reduced the activity of the tissue factor pathway inhibitor. Foam cell formation was induced by GroEL. GroEL-injected ApoE(-/-) mice showed significant atherosclerotic lesion progression compared with control mice. Serum levels of risk factors for atherosclerosis such as interleukin-6, C-reactive protein, and low-density lipoprotein were increased in GroEL-injected ApoE(-/-) mice compared with control mice, whereas serum levels of high-density lipoprotein were decreased. We could detect significantly higher levels of anti-F. nucleatum GroEL antibody in serum and F. nucleatum DNA in gingival crevicular fluid from patients with periodontitis than in that from healthy subjects. Our results indicate that the host response to the GroEL of periodontal pathogens like F. nucleatum may be a mechanism involved in atherosclerosis, supporting the association of periodontitis and systemic infection.

Immunological impact of Taekwondo competitions.

Immunological changes in elite adolescent female athletes during Taekwondo competitions were investigated on-field. 6 female athletes (16.7 ± 0.8 year-old) volunteered and performed 5 bouts of demonstration Taekwondo competitions simulating real tournaments in intensity, duration, and break-time intervals on the same day. Blood samples were taken before, after the competitions and during the recovery, respectively. Immunological changes and oxidative stress in peripheral blood mononuclear cells were evaluated by flow-cytometry. During the competitions, exercise intensity was 92.2 ± 3.8% (86.1~95.7) of the maximal heart rate. Blood lactate increased immediately after the competitions (p=0.0165) and decreased to baseline during recovery. Intracellular reactive oxygen species (ROS) in the peripheral blood increased continuously during recovery (p<0.05, respectively). Natural killer cells increased immediately after the competitions (p=0.0006), and decreased during recovery. B and T cells increased immediately after the competitions and remained elevated throughout recovery (p<0.05, respectively). CD4/CD8 ratio after the competitions was decreased (p=0.0091) and returned to baseline during recovery. These results suggest that the immunological function of the elite female adolescent athletes could be attenuated after Taekwondo competitions. Further large-scaled Taekwondo studies on immunologic and apoptotic changes related to oxidative stress should be performed for improving and protecting the health of adolescent athletes.

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest.

The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

In-vivo-induced antigenic determinants of Fusobacterium nucleatum subsp. nucleatum.

Fusobacterium nucleatum plays a pivotal role in dental plaque biofilm formation and is known to be involved in chronic inflammatory systemic disease. However, limited knowledge of F. nucleatum genes expressed in vivo interferes with our understanding of pathogenesis. In this study, we identified F. nucleatum genes induced in vivo using in-vivo-induced antigen technology (IVIAT). Among 30,000 recombinant clones screened, 87 reacted reproducibly with pooled sera from 10 patients with periodontitis. The clones encoded for 32 different proteins, of which 28 could be assigned to their functions, which were categorized in translation, transcription, transport, energy metabolism, cell envelope, cellular process, fatty acid and phospholipid metabolism, transposition, cofactor biosynthesis, amino acid biosynthesis, and DNA replication. Putative virulence factors detected were ABC transporter, butyrate-acetoacetate CoA-transferase, hemin receptor, hemolysin, hemolysin-related protein, LysR family transcriptional regulator, serine protease, and transposase. Analysis of immune responses to the in-vivo-induced (ivi) antigens in five patients demonstrated that most were reactive to these proteins, confirming results with pooled sera. IVIAT-identified F. nucleatum genes in this study may accelerate the elucidation of F. nucleatum-mediated molecular pathogenesis.

RKKY ferromagnetism with Ising-like spin states in intercalated Fe(1/4)TaS2.

We investigated the magnetic nature of Fe(1/4)TaS2 using x-ray absorption spectroscopy, photoemission spectroscopy, and first principles band calculations. The results show a large unquenched orbital magnetic moment (∼1.0 µ(B)/Fe) at intercalated Fe sites, resulting in a gigantic magnetic anisotropy (H(A)≃60 T). The magnetic coupling is well understood in terms of the Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction, suggesting a novel RKKY ferromagnet with Ising-type spin states. We also found that this indirect exchange coupling between the neighboring Fe spins is ferromagnetic and maximized at the Fe-Fe distance of 2×2 superstructure.

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control.

OBJECTIVE: To investigate whether drugs targeting peripheral cannabinoid-1 (CB1) receptor ameliorate adiposity comparable to central CB1-receptor antagonist or not. MEASUREMENTS: Receptor binding assay and functional assay in vitro. Pharmacokinetic parameters in mice, brain uptake clearance of compounds in rats and antagonism on the CB1-agonist-induced hypothermia in mice. Diet consumption, body weight changes, hepatic gene expression of sterol-regulatory element-binding protein-1 (SREBP-1) and plasma/tissue concentrations of compounds in HF diet-induced obese (HF-DIO) mice after acute and chronic treatment. RESULTS: Compound-1, an SR141716A derivative, is a peripheral CB1-receptor-selective antagonist that is 10 times less potent than SR141716A in in vitro evaluations. Although the plasma concentrations of Compound-1 are five times higher than those of SR141716A, its potency is still 10 times lower than that of SR141716A in reducing the consumption of normal or HF diet by mice. Through evaluations of brain uptake and the effect on CB1-agonist-induced hypothermia, it was verified that the blood-brain barrier (BBB) penetration of Compound-1 is much lower than that of SR141716A. In HF-DIO mice, chronic treatment by Compound-1 showed dose-dependent antiobesity activities, while its brain distribution was very low as compared with that of SR141716A. Compound-1's effective doses for antiobesity activity were just over 30 mg kg(-1). However, Compound-1 completely suppressed the elevated hepatic SREBP-1 expression even at 10 mg kg(-1). CONCLUSION: These results suggest that (1) central CB1 receptors mediate anorectic response of CB1-receptor antagonists and (2) peripheral modulations, including SREBP-1 expression, are not major mechanisms in the antiobesity effects of CB1-receptor antagonists.

Direct observation of dispersive Kondo resonance peaks in a heavy-fermion system.

Ce 4d-4f resonant angle-resolved photoemission spectroscopy was carried out to study the electronic structure of strongly correlated Ce 4f electrons in a quasi-two-dimensional nonmagnetic heavy-fermion system CeCoGe1.2Si0.8. For the first time, dispersive coherent peaks of an f state crossing the Fermi level, the so-called Kondo resonance, are directly observed together with the hybridized conduction band. Moreover, the experimental band dispersion is quantitatively in good agreement with a simple hybridization-band picture based on the periodic Anderson model. The obtained physical quantities, i.e., coherent temperature, Kondo temperature, and mass enhancement, are comparable to the results of thermodynamic measurements. These results manifest an itinerant nature of Ce 4f electrons in heavy-fermion systems and clarify their microscopic hybridization mechanism.

Effect of linear density of states on the quasiparticle dynamics and small electron-phonon coupling in graphite.

We obtained the spectral function of very high quality natural graphite single crystals using angle-resolved photoelectron spectroscopy. A clear separation of nonbonding and bonding bands and asymmetric lineshape are observed. The asymmetric line shapes are well accounted for by the finite photoelectron escape depth and the band structure. The extracted width of the spectral function (inverse of the photohole life time) near the K point is, beyond the maximum phonon energy, approximately proportional to the energy as expected from the linear density of states near the Fermi energy. The upper bound for the electron-phonon coupling constant is about 0.2, a much smaller value than the previously reported one.

Efficacy and prognosis of a short course of prednisolone therapy for pediatric epilepsy.

PURPOSE: To evaluate the efficacy and safety of adjunctive prednisolone therapy in children with cryptogenic epileptic encephalopathy, other than infantile spasms, and to determine its prognosis. METHODS: Prednisolone, 2mg/kg per day for 6 weeks, tapered for a further 2 weeks, was given in combination with previously prescribed antiepileptic drugs. A retrospective assessment of 41 children thus treated included measurements of seizure frequency, electroencephalographic findings, global assessments of cognitive function, and adverse drug events. Long-term patient prognoses over a mean follow-up period of 3 years and 5 months (range, 14-90 months) were also examined. RESULTS: Of 41 patients, 32 had Lennox-Gastaut syndrome, 4 had Doose syndrome, 1 had Otahara syndrome, 2 had Landau-Kleffner syndrome, and 2 had other unspecified generalized epilepsies. After prednisolone therapy, 73% (30/41) of patients showed a reduction in seizure frequency of >50%, and 59% (24/41) became seizure free. However, only seven patients (four with Lennox-Gastaut syndrome, two with Doose syndrome, and one with unspecified generalized epilepsy) who became seizure free remained free of seizures at the time of the final follow-up. Electroencephalographic findings and global assessments of cognitive function correlated well with seizure outcomes. No significant demographic factors influenced the efficacy of prednisolone or patient prognoses after prednisolone tapering. Most adverse events were transient, or were tolerated well with conservative management, with maintenance of the medication. CONCLUSION: Prednisolone therapy may be a safe and effective adjunct in patients with cryptogenic epileptic encephalopathies, but the high relapse rate is of concern.

An orally active cathepsin K inhibitor, furan-2-carboxylic acid, 1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide (OST-4077), inhibits osteoclast activity in vitro and bone loss in ovariectomized rats.

Human cathepsin K, a cysteine proteinase of the papain family, has been recognized as a potential drug target for the treatment of osteoporosis. The predominant expression of cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel antiresorptive drugs. Now, we report the pharmacological properties of OST-4077 [furan-2-carboxylic acid (1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide] as a novel selective cathepsin K inhibitor. Human and rat cathepsin K were inhibited in vitro by OST-4077 with the IC50 values of 11 and 427 nM, respectively. OST-4077 suppressed bone resorption induced by rabbit osteoclasts (IC50, 37 nM) but did not affect bone mineralization or cellular alkaline phosphatase activity in MC3T3-E1 cells. Parathyroid hormone-induced bone resorption was inhibited in a dose-dependent manner in thyroparathyroidectomized rats gavaged with a single dose of OST-4077 (ED50, 69 mg/kg). When given orally twice daily for 4 weeks to 3-month-old ovariectomized (OVX) rats, OST-4077 dose-dependently prevented bone loss, as monitored by bone densitometry, ash content, and urinary excretion of deoxypyridinoline. No change in serum osteocalcin in the OVX rats by OST-4077 suggested that bone formation might not be affected by the agent. In summary, OST-4077 selectively inhibited bone resorbing activities of osteoclasts and prevented bone loss induced by estrogen deficiency but did not affect bone formation. OST-4077, an orally active selective human cathepsin K inhibitor, may have the therapeutic potential for the treatment of diseases characterized by excessive bone loss including osteoporosis.