Is there an obesity paradox in the Japanese elderly population? A community-based cohort study of 13 280 men and women.

AIM: Despite increased interest in an obesity paradox (i.e. a survival advantage of being obese), evidence remains sparse in Japanese populations. We aimed to verify this phenomenon among community-dwelling older adults in Japan. METHODS: Older adults aged 65-84 years randomly chosen from all 74 municipalities in Shizuoka Prefecture completed questionnaires including body mass index information. Participants were followed from 1999 to 2009. Following World Health Organization guidelines, participants were classified using an appropriate body mass index for Asian populations as follows: <18.5 kg/m2 (underweight), 18.5-23.0 kg/m2 (normal weight), 23.0-27.5 kg/m2 (overweight) and ≥27.5 kg/m2 (obesity). We estimated hazard ratios and their 95% confidence intervals for all-cause mortality, controlling for sex, age, smoking status, alcohol consumption, physical activity, hypertension and diabetes mellitus. RESULTS: Compared with normal-weight participants, overweight/obese participants tended to have lower hazard ratios; the multivariate hazard ratios (95% confidence interval) were 0.86 (0.62-1.19) for obesity, 0.83 (0.73-0.94) for overweight and 1.60 (1.40-1.82) for underweight. In subgroup analyses by sex and age, the hazard ratios tended to be lower among obese men, albeit not significantly; hazard ratios (95% confidence interval) were 0.56 (0.25-1.27) in men aged 65-74 years, and 0.78 (0.41-1.45) in men aged 75-84 years. CONCLUSIONS: The present study provides evidence of a conservative obesity paradox among older Japanese people, using the appropriate body mass index cut-off points for Asian populations. In particular, obese older men tend to have a lower risk of all-cause mortality. Geriatr Gerontol Int 2017; 17: 1257-1264.

Long-term exposure to traffic-related air pollution and the risk of death from hemorrhagic stroke and lung cancer in Shizuoka, Japan.

A number of studies have linked exposure to long-term outdoor air pollution with cardiopulmonary disease; however, the evidence for stroke is limited. Furthermore, evidence with the risk for lung cancer (LC) is still inconsistent. We, therefore, evaluated the association between long-term exposure to traffic-related air pollution and cause-specific mortality. Individual data were extracted from participants of an ongoing cohort study in Shizuoka, Japan. A total of 14,001 elderly residents completed questionnaires and were followed from December 1999 to January 2009. Annual individual nitrogen dioxide (NO(2)) exposure data, as an index for traffic-related exposure, were modeled using a Land Use Regression model and assigned to the participants. We then estimated the adjusted hazard ratios (HRs) and their confidence intervals (CIs) associated with a 10 µg/m(3) elevation in NO(2) for all-cause or cause-specific mortality using time-varying Cox proportional hazards models. We found positive associations of NO(2) levels with all-cause (HR=1.12, 95% CI: 1.07-1.18), cardiopulmonary disease (HR=1.22, 95% CI: 1.15-1.30), and LC mortality (HR=1.20, 95% CI: 1.03-1.40). Among cardiopulmonary disease mortality, not only the risk for ischemic heart disease (HR=1.27, 95% CI: 1.11-1.47) but also the risks for stroke were elevated: intracerebral hemorrhage (HR=1.28, 95% CI: 1.05-1.57) and ischemic stroke (HR=1.20, 95% CI: 1.04-1.39). The present study supports the existing evidence that long-term exposure to traffic-related air pollution increases the risk of cardiopulmonary as well as LC mortality, and provides additional evidence for adverse effects on intracerebral hemorrhage as well as ischemic stroke.

Does habitual physical activity prevent insomnia? A cross-sectional and longitudinal study of elderly Japanese.

Few epidemiological studies have examined the potential protective effects of physical activity on insomnia. The authors thus evaluated the association between physical activity and insomnia in a large population-based study in Shizuoka, Japan. Individual data were obtained from participants in an ongoing cohort study. A total of 14,001 older residents who completed questionnaires were followed for 3 yr. Of these, 10,211 and 3,697 participants were eligible for the cross-sectional and longitudinal analyses, respectively. The authors obtained information about the frequency of physical activity and insomnia. Then, the adjusted odds ratios and 95% confidence intervals between physical activity and insomnia were estimated. Habitual physical activity was related to lower prevalence of insomnia. Frequent physical activity also reduced the incidence of insomnia, especially difficulty maintaining sleep. For elderly people with sufficient mobility and no preexisting disease, high-frequency physical activity (e.g., 5 or more days/wk) may help reduce insomnia.

[Relationship between cognitive function and physical activities: a longitudinal study among community-dwelling elderly].

AIM: The purpose of this study was to evaluate whether physical activities reduce the risk of cognitive decline in community-dwelling elderly. We investigated correlations between cognitive functions at baseline and physical activities, correlations between cognitive functions at baseline and cognitive decline over 4 years, as well as correlations between physical activity at baseline and cognitive decline over 4 years. METHODS: At baseline, 2,431 community-dwelling elderly completed the cognitive screening by telephone (TICS-J), and answered the questionnaires about physical activities. Of these, 1,040 subjects again completed the TICS-J over 4 years. Physical activities contained moving ability, walking frequency, walking speed, the exercise frequency. RESULTS: At baseline, 870 elderly (age 75.87±4.96 (mean±SD) years, duration of education 11.05±2.41) showed normal cognitive functions and 170 (79.19±6.22, 9.61±2.23) showed cognitive impairment. The total TICS-J score was significantly higher in cognitive normal subjects compared with that of cognitive impaired subjects (36.02±1.89, 30.19±2.25, respectively, p<0.001). Logistic regression analyses showed that moving ability significantly reduced the risk of cognitive impairment in an unadjusted model, and walking speed also reduced the risk of cognitive impairment at baseline even in an adjusted model. Cognitive function at baseline might be a predictor of cognitive function over 4 years. The longitudinal study revealed that walking speed and exercise frequency significantly correlate with maintenance of cognitive function over 4 years. CONCLUSIONS: This study provides that physical activities, especially walking speed have significant correlation with cognitive function.

[Relationship between quality of life and chronic illnesses in community-dwelling elderly people].

AIM: Chronic illnesses are common among elderly people, and may considerably affect to their quality of life (QOL). We investigated the impact of chronic conditions on QOL among community-dwelling elderly people, and the stability of QOL over time. METHODS: A total of 2,762 community-dwelling elderly persons (men: 47.0%, age 76.7±5.8 [mean±SD]) completed postal QOL questionnaires twice over 4 years. Chronic illnesses were selected from the following 9 conditions: cerebrovascular disease, hypertension, heart disease, cancer, diabetes mellitus, bone fracture, chronic digestive disease, chronic respiratory disease, and the diseases of joints or muscles. The QOL questionnaire was developed based on the QOL components proposed by Lawton, and consisted of 6 subscales: daily activity, health satisfaction, human support satisfaction, economic state satisfaction, symptoms of depression, and positive mental attitude. The subjects were divided into 3 groups regardless of the presence of chronic illnesses. QOL subscale scores were compared among the 3 groups, and fluctuations over 4 years were also evaluated. RESULTS: The baseline QOL scores showed significant differences among the 3 groups, especially regarding health satisfaction, but not in satisfaction with human support. There were significant differences among the 3 groups in fluctuations over 4 years in health satisfaction, daily activity, and positive mental attitude. CONCLUSIONS: Chronic illnesses have a negative impact on the QOL of elderly people, and also influence fluctuations in QOL over time. Degrees of impacts differed according to each QOL subscale. Therefore, evaluation of QOL in community-dwelling elderly needs multi-dimensional assessment.

Physical activity and mortality risk in the Japanese elderly: a cohort study.

BACKGROUND: Physical activity recommendations for older adults with poor health needs to be understood. PURPOSE: This study aims to examine the association between the frequency of physical activity and mortality among a sample of elderly subjects, most of whom were under treatment for pre-existing disease. METHODS: Data on the frequency of leisure-time physical activity, walking for transportation, and non-exercise physical activity were obtained from a population-based cohort study in Shizuoka, Japan. Of the randomly selected 22,200 residents aged 65-84 years, 10,385 subjects were followed from 1999 to 2006 and analyzed. Hazard ratios (HRs) and 95% CIs were obtained for all-cause; cardiovascular disease (CVD); and cancer mortality, after adjusting for covariates such as pre-existing disease(s). A subgroup analysis that was restricted to subjects under treatment for pre-existing disease(s) at baseline was further conducted. Data were collected between 1999 and 2006, and all analyses were conducted in 2008 and 2009. RESULTS: Every physical activity was associated with a reduced risk of all-cause and CVD mortality, among not only the total sample but even those under treatment. The HRs for CVD mortality among participants with 5 or more days of non-exercise physical activity per week for the total sample and those with pre-existing disease(s) were 0.38 (95% CI=0.22, 0.55) and 0.35 (95% CI=0.24, 0.52), respectively, compared with no non-exercise physical activity. The association between physical activity and cancer mortality was not clear. CONCLUSIONS: This study suggests a protective effect of physical activity on all-cause and CVD mortality among Japanese elderly people with pre-existing disease.

Beneficial effect of physical activity on blood pressure and blood glucose among Japanese male workers.

AIMS: To examine the appropriate type and frequency of physical activity for the beneficial effect on hypertension and hyperglycemia. METHODS: The incidence of hypertension and hyperglycemia was assessed using the results of annual physical checkups over 4 years for 5843 male employees aged 18-57 years old. Associations of different types of physical activity with the incidence of these two risk factors were examined with Cox proportional-hazard models. RESULTS: There was a progressive reduction in the hazards ratios of hypertension with increasing total daily activity (hazards ratio of 0.65 (95% CI, 0.45-0.93) in subjects who walked >8000 steps/day vs. <4000 steps/day). Subjects who exercised >3 times/week also showed a significantly lower risk (0.35; 0.13-0.96) of developing hypertension vs. those who exercised <3 times/week. The only physical activity factor associated with a lower incidence of hyperglycemia was weekend (Saturday and Sunday) physical activity (0.66; 0.43-0.99, very active vs. sedentary on weekends). CONCLUSION: Increasing daily and leisure time physical activities had a beneficial effect on hypertension independent from physical activity at weekend, while only doing physical activity on weekends affects an elevation of blood glucose independent of daily and leisure time physical activity.

Long-term exposure to traffic-related air pollution and mortality in Shizuoka, Japan.

OBJECTIVES: The number of studies investigating the health effects of long-term exposure to air pollution is increasing, however, most studies have been conducted in Western countries. The health status of Asian populations may be different to that of Western populations and may, therefore, respond differently to air pollution exposure. Therefore, we evaluated the health effects of long-term exposure to traffic-related air pollution in Shizuoka, Japan. METHODS: Individual data were extracted from participants of an ongoing cohort study. A total of 14,001 older residents, who were randomly chosen from all 74 municipalities of Shizuoka, completed questionnaires and were followed from December 1999 to March 2006. Individual nitrogen dioxide exposure data, as an index for traffic-related exposure, were modelled using a land use regression model. We assigned participants an estimated concentration of nitrogen dioxide exposure during 2000-2006. We then estimated the adjusted HR and their CI for a 10 microg/m(3) increase in exposure to nitrogen dioxide for all-cause or cause-specific mortality. RESULTS: The adjusted HR for all-cause mortality was 1.02 (95% CI 0.96 to 1.08). Regarding cause-specific mortality, the adjusted HR for cardiopulmonary mortality was 1.16 (95% CI 1.06 to 1.26); in particular the adjusted HR for ischaemic heart disease mortality was 1.27 (95% CI 1.02 to 1.58) and for pulmonary disease mortality it was 1.19 (95% CI 1.02 to 1.38). Furthermore, among non-smokers, a 10 microg/m(3) increase in nitrogen dioxide was associated with a higher risk for lung cancer mortality (HR 1.30, 95% CI 0.85 to 1.93). CONCLUSION: Long-term exposure to traffic-related air pollution, indexed by nitrogen dioxide concentration, increases the risk of cardiopulmonary mortality, even in a population with a relatively low body mass index and increases the risk of lung cancer mortality in non-smokers.

Green tea consumption and mortality among Japanese elderly people: the prospective Shizuoka elderly cohort.

PURPOSE: To investigate the association between green tea consumption and mortality from all causes, cancer, and cardiovascular disease (CVD) among elderly people. METHODS: In a population-based, prospective cohort study, a total of 14,001 elderly residents (aged 65-84 years), randomly chosen from all 74 municipalities in Shizuoka, Japan, completed questionnaires that included items about frequency of green tea consumption. They were followed for up to 6 years, from December 1999 to March 2006. Consequently, 12,251 subjects were analyzed to estimate the hazard ratios (HRs) for all-cause mortality, cancer, and CVD. RESULTS: Among 64,002 person-years, 1,224 deaths were identified (follow-up rate, 71.6%). The multivariate HRs and 95% confidence intervals (CIs) for CVD mortality compared those who consumed seven or more cups per day with those who consumed less than one cup per day, were 0.24 (0.14-0.40), 0.30 (0.15-0.61), and 0.18 (0.08-0.40) for total participants, men, and women, respectively. Although green tea consumption was not inversely associated with cancer mortality, green tea consumption and colorectal cancer mortality were inversely associated with a moderate dose-response relationship. CONCLUSIONS: Green tea consumption is associated with reduced mortality from all causes and CVD. This study also suggests that green tea could have protective effects against colorectal cancer.

Sleep duration, sleep quality and cardiovascular disease mortality among the elderly: a population-based cohort study.

OBJECTIVE: To investigate the associations between sleep duration and mortality in the elderly by controlling for sleep quality. METHOD: Data were collected from participants in a cohort study in Shizuoka, Japan. A total of 14,001 elderly residents (aged 65-85 years), randomly chosen from all 74 municipalities in the prefecture, completed questionnaires that evaluated sleep duration, sleep complaints, and the use of hypnotics. Participants were followed from 1999 to 2006. We analyzed 11,395 subjects to estimate the hazard ratios (HR) for mortality from all causes and cardiovascular disease (CVD). RESULTS: With 60,252 person-years, 1004 deaths were identified. While short sleep duration and mortality were not associated, longer sleep duration was associated with higher risk of mortality in both sexes. Compared with those who slept 7 h, the multivariate HR and 95% confidence interval of CVD mortality for those who slept > or =10 h was 1.95 (1.18-3.21) and, for those who slept < or =5 h, it was 1.10 (0.62-1.93). Although no clear association was found between sleep quality and mortality, long sleep duration was associated with higher risk of CVD mortality among those with poor sleep quality. CONCLUSION: Long sleep duration is associated with higher risk of CVD mortality among the elderly with poor sleep quality.

[Relationship between Quality of Life (QOL) and cognitive function among community-dwelling elderly].

AIM: It has become important for elderly to live better rather than to live longer. There have been many reports about quality of life (QOL) of the elderly, but we have no knowledge about the relation between the QOL and the cognitive function. We investigated the relationship between the QOL and the cognitive function among community-dwelling elderly. METHODS: A total of 12,059 community-dwelling elderly were invited to join a cognitive screening study by telephone (TICS-J) combined with a mailed QOL questionnaire. Among them, 1,920 subjects (age 71.87+/-5.50 (mean+/-SD) years old, duration of education 11.08+/-2.61 years) who completed both TICS-J and QOL questionnaire were actually measured. TICS-J was administered by the previously reported method, and the QOL questionnaire was developed based on the component of QOL proposed by Lawton, and consisted of 6 subscales (daily activity, satisfaction with health, satisfaction with human support, satisfaction with economic state, symptoms of depression, and positive mental attitude). Correlations were analyzed among the scores of TICS-J, age, duration of education, and scores on each QOL subscale. Multiple linear regression analysis was conducted after QOL subscale scores, adjusting for gender, age, and duration of education, were entered as dependent variables. RESULTS: Four out of 6 subscales scores of QOL showed significant differences between men and women. All QOL subscale scores showed significant differences between the two groups in the TICS-J scores. Partial correlations were seen among TICS-J scores and each QOL subscale score. Multiple linear regression analysis revealed significant influence of cognitive function by TICS-J on QOL subscales scores. CONCLUSIONS: Cognitive function was considered to have more influence on QOL scores than gender or age. TICS-J and the QOL questionnaire in this study were useful to evaluate the outcome of welfare in community-dwelling elderly.

Screening for methicillin-resistant Staphylococcus aureus (MRSA) carriage on admission to a geriatric hospital.

Our objective is to identify risk factors for carriage of MRSA on admission to a geriatric hospital where MRSA is endemic. A prospective screening for MRSA carriage was conducted by swabbing anterior nares and anal skin for 6 weeks. One hundred and thirty-eight patients aged over 65 were enrolled after obtaining their informed consent. Swabs of anterior nares and anal skin of patients were submitted for culture for MRSA. The demographic, administrative, and clinical data for each participant were recorded, and their association with MRSA carriage was determined by stepwise regression analysis. MRSA was recovered from 11 patients (11/138 patients, 8.0%), and from anal skin in 8 of them. Without screening of anal skin, 5 out of 11 carriers had been missed. Multivariate analysis revealed that hypoalbuminemia (adjusted risk ratio, RR=6.39, 95% confidence interval, CI=1.08-37.84) and bedridden status (RR=8.26, CI=1.04-65.31) were independent risk factors. Screening of elderly patients for gastrointestinal colonization on admission had implications for early detection of the reservoir of MRSA. Systematic selective screening for MRSA carriage targeting high-risk patients with hypoalbuminemia or bedridden status would be useful for infection control of this resistant organism.

[Cognitive function screening of community-dwelling elderly by Telephone Interview for Cognitive Status in Japanese (TICS-J)].

AIM: The purpose of this study was to evaluate whether the Telephone Interview for Cognitive Status in Japanese (TICS-J) is accepted among community-dwelling elderly, to examine the correlations among gender, age or the duration of education and the TICS-J, as well as to grasp the subjects with probable cognitive impairment. METHODS: A total of 12,059 community-dwelling elderly were invited to join the cognitive screening by the TICS-J, among which 3,482 responded, of these we were actually able to measure 2,620 and found out the educational back ground of the 2,431. They counted 1,186 men (age 72.3+/-5.7 (mean+/-SD) years old, duration of education 11.4+/-2.9 years) and 1,245 women (72.4+/-5.8, 10.3+/-2.2). The TICS-J was administered according to the TICS manual. The TICS-J consisted of orientation concerning name, time and place, counting backward from 20 to 1, remembering a word list, 7 serial subtractions, naming of verbal descriptions, repetition, recent memory, praxis and opposites. The subjects were divided into two groups by the duration of education (less than 11 years, or 11 years or more), or four groups by age (65-69, 70-74, 75-79 and 80 years old or more). RESULTS: There were no significant differences of total TICS-J scores between men and women, 34.3+/-3.5 and 34.4+/-3.6, respectively. The mean total score of the high education group (35.3+/-3.0) was significantly higher than that of the low education group (33.3+/-3.8). Moreover, the averages of the total scores decreased according to age increase. The number of the subjects who showed the total TICS-J scores below the cut-off point of 33 was 564 (23.2%). CONCLUSIONS: There was no difference between men and women with the average total score of the TICS-J, however, there were correlations between ages and extent of education and their average total scores. The TICS-J is useful to assess the cognitive function of the community-dwelling elderly.

[Exercise therapy for patients with mild hypertension].

We reviewed exercise therapy of mild hypertension, a way of thinking for exercise therapy, and exercise prescription. Hypotensive effect of mild to moderate aerobic exercise was evident. Our previous report revealed that more than 60 minutes exercise a week was sufficient to decrease blood pressure. Another our study showed that hypotensive effect was less in older subjects than in younger group, but another study showed that blood pressure decreased even during 3 to 9 months after the beginning of exercise therapy. These findings might indicate that decrease in blood pressure in the elderly was slower than in younger subjects.

Postural stability and physical performance in social dancers.

This cross-sectional study examined the benefits of social dancing on postural stability and physical performance in dancers aged 50 years or more. Walking speed, lower limb reaction time and low back flexibility were measured in 202 social dancers and 202 community-dwelling comparison subjects aged 50-87 years. The results showed that dancers who were older than 60 years had better postural stability and faster leg reaction times, whilst dancers aged 50-59 showed only better flexibility, when compared with the controls. Male dancers had greater low back flexibility and leg reaction time compared to controls. In contrast, female dancers had superior performance only for leg reaction time when compared with controls. The results indicate that social dancing is associated with enhanced postural stability and physical performance in older adults.

Platelet-derived growth factor-BB amplifies PGF2alpha-stimulated VEGF synthesis in osteoblasts: function of phosphatidylinositol 3-kinase.

We have reported that prostaglandin F2alpha (PGF2alpha) stimulates the synthesis of vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. In addition, we recently showed that phosphatidylinositol 3 (PI3)-kinase activated by platelet-derived growth factor-BB (PDGF-BB) negatively regulates the interleukin-6 synthesis in these cells. In the present study, we investigated the effect of PDGF-BB on the PGF2alpha-induced VEGF synthesis in MC3T3-E1 cells. PDGF-BB, which alone did not affect the levels of VEGF, significantly enhanced the PGF2alpha-stimulated VEGF synthesis. The amplifying effect of PDGF-BB was dose dependent in the range between 10 and 70 ng/ml. LY294002 or wortmannin, specific inhibitors of PI3-kinase, which by itself failed to affect the PGF2alpha-stimulated VEGF synthesis, significantly suppressed the amplification by PDGF-BB. PD98059, a specific inhibitor of MEK1/2, suppressed the amplification by PDGF-BB of the PGF2alpha-stimulated VEGF synthesis similar to the levels of PGF2alpha with PD98059. PDGF-BB itself induced the phosphorylation of p44/p42 MAP kinase in these cells, and the effects of PDGF-BB and PGF2alpha on the phosphorylation of p44/p42 MAP kinase were additive. Moreover, LY294002 had little effect on the phosphorylation of p44/p42 MAP kinase induced by PGF2alpha with PDGF-BB. These results strongly suggest that PGF2alpha-stimulated VEGF synthesis is amplified by PI3-kinase-mediating PDGF-BB signaling in osteoblasts, and that the effect is exerted at a point downstream from p44/p42 MAP kinase.

Validation of the Telephone Interview for Cognitive Status (TICS) in Japanese.

BACKGROUND: In recent years, the population of elderly people in Japan with dementia has increased. Detection of cognitive impairment in the early stages is important for adequate treatment, care, and prevention. AIM: To investigate whether the reliability and validity of the instrument would carry over to a different population and language before using it for population-based epidemiological studies. METHODS: We studied 135 subjects, 49 patients with Alzheimer's disease (AD) and 86 healthy controls (CTL) using the Telephone Interview for Cognitive Status (TICS) and developed the Japanese version of the TICS (TICS-J). We also evaluated combination of another telephone battery, the Category Fluency Test (CF). RESULTS: The sensitivity and specificity of the TICS-J to differentiate AD patients from CTL was 98.0% and 90.7%, respectively. Pearson's correlation coefficient for the TICS-J and Mini-Mental State Examination (MMSE) was 0.858 (p < 0.001). On the Receiver Operating Characteristic (ROC), the area under the curve for the TICS-J was 98.7%. The combination of the TICS-J with the CF did not change the validity of the discrimination. CONCLUSION: These results indicated that TICS-J was a sensitive and specific instrument for differentiating AD patients from healthy controls.

(-)-Epigallocatechin gallate suppresses endothelin-1-induced interleukin-6 synthesis in osteoblasts: inhibition of p44/p42 MAP kinase activation.

We previously showed that endothelin-1 (ET-1) stimulates the synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells, and that protein kinase C (PKC)-dependent p44/p42 mitogen-activated protein (MAP) kinase plays a part in the IL-6 synthesis. In the present study, we investigated the effect of (-)-epigallocatechin gallate (EGCG), one of the major flavonoids containing in green tea, on ET-1-induced IL-6 synthesis in osteoblasts and the underlying mechanism. EGCG significantly reduced the synthesis of IL-6 stimulated by ET-1 in MC3T3-E1 cells as well primary cultured mouse osteoblasts. SB203580, a specific inhibitor of p38 MAP kinase, but not SP600125, a specific SAPK/JNK inhibitor, suppressed ET-1-stimulated IL-6 synthesis. ET-1-induced phosphorylation of p38 MAP kinase was not affected by EGCG. On the other hand, EGCG suppressed the phosphorylation of p44/p42 MAP kinase induced by ET-1. Both the IL-6 synthesis and the phosphorylation of p44/p42 MAP kinase stimulated by 12-O-tetradecanoylphorbol 13-acetate (TPA), a direct activator of PKC, were markedly suppressed by EGCG. The phosphorylation of MEK1/2 and Raf-1 induced by ET-1 or TPA were also inhibited by EGCG. These results strongly suggest that EGCG inhibits ET-1-stimulated synthesis of IL-6 via suppression of p44/p42 MAP kinase pathway in osteoblasts, and the inhibitory effect is exerted at a point between PKC and Raf-1 in the ET-1 signaling cascade.