Impaired bone resorption by lipopolysaccharide in vivo in mice deficient in the prostaglandin E receptor EP4 subtype.

In a previous study we showed that the involvement of EP4 subtype of the prostaglandin E (PGE) receptor is crucial for lipopolysaccharide (LPS)-induced osteoclast formation in vitro. The present study was undertaken to test whether EP4 is actually associated with LPS-induced bone resorption in vivo. In wild-type (WT) mice, osteoclast formation in vertebrae and tibiae increased 5 days after systemic LPS injection, and urinary excretion of deoxypyridinoline, a sensitive marker for bone resorption, statistically increased 10 days after injection. In EP4 knockout (KO) mice, however, LPS injection caused no significant changes in these parameters throughout the experiment. LPS exposure for 4 h strongly induced osteoclast differentiation factor (ODF) mRNA expression in primary osteoblastic cells (POB) both from WT and EP4 KO mice, and this expression was not inhibited by indomethacin, suggesting prostaglandin (PG) independence. LPS exposure for 24 h further induced ODF expression in WT POB, but not in EP4 KO POB. Indomethacin partially inhibited ODF expression in WT POB, but not in EP4 KO POB. These data suggest that ODF is induced both PG dependently and PG independently. LPS exposure for 24 h induced slightly greater osteoclastgenesis inhibitory factor (OCIF) mRNA expression in EP4 KO than in WT POB. These findings suggest that the reduced ODF expression and apparently increased OCIF expression also are responsible for the markedly reduced LPS-induced osteoclast formation in EP4 KO mice. Our results show that the EP4 subtype of the PGE receptor is involved in LPS-induced bone resorption in vivo also. Since LPS is considered to be largely involved in bacterially induced bone loss, such as in periodontitis and osteomyelitis, our study is expected to help broaden our understanding of the pathophysiology of these conditions.

Prostaglandin E(2) (PGE(2)) induces the c-fos and c-jun expressions via the EP(1) subtype of PGE receptor in mouse osteoblastic MC3T3-E1 cells.

This study examined which subtype(s) of PGE receptors is involved in the induction of c-fos and c-jun by PGE(2) in MC3T3-E1 cells. We also investigated the possibility that the induction of these genes is involved in the growth and differentiation of this cell line. PGE(2) dose-dependently induced c-fos and c-jun mRNA expressions in MC3T3-E1 cells. Of the PGE analogs, 17-phenyl-omega-trinor PGE(2) (EP(1) agonist) and sulprostone (EP(1)/EP(3) agonist) were far more potent than butaprost (EP(2) agonist) and 11-deoxy PGE(1) (EP(2)/EP(4) agonist) in inducing c-fos and c-jun mRNA expressions. Since MC3T3-E1 cells do not express the EP(3) subtype, these results suggest that PGE(2) induces c-fos and c-jun mRNA expressions through the EP(1) subtype of its receptor. In order to study the functional relevance of these protooncogenes, we then studied the effect of inhibition of their synthesis by the use of antisense oligonucleotide. Alkaline phosphatase (ALP) suppression by 17-phenyl-omega-trinor PGE(2) was reversed by antisense oligonucleotide for either c-fos or c-jun. These results suggest that PGE(2), via the EP(1) subtype of the PGE receptor, negatively modulates the transition from proliferation to the matrix maturation stage through the induction of c-fos and c-jun. However, antisense oligonucleotide for c-fos or c-jun did not alter the prostaglandin G/H synthase-2 mRNA expression induced by EP(1). Thus, it is possible that c-fos and c-jun inductions do not account for all the EP(1)-mediated PGE(2) actions in MC3T3-E1 cells.

[The relation of physical and mental stress to magnesium deficiency in patients with variant angina].

In this study we assessed the role of psychological factor in the etiology of coronary vasospasm using the Cornell Medical Index (CMI), focusing attention on the relationship between stress and serum magnesium (Mg). The study subjects consisted of 25 patients with variant angina (VA), 32 with old myocardial infarction without vasospasm (OMI), and 34 healthy men (controls). On a neurosis-discriminative diagram of CMI, areas I and II were considered as normal and areas III and IV were considered to be a neurotic disorder. The stress test included exercise and a quiz. Exercise test was performed in 8 patients with VA, 6 with OMI, and 5 controls, and a quiz was given to 4 patients with VA. Plasma catecholamines [noradrenaline (NA), adrenaline (Ad), dopamine], aldosterone, adrenocorticotropic hormone (ACTH) and serum electrolytes (Mg, Ca, Na, K, Cl) were measured before and after exposures to stress. The following results were obtained: 1) Of the patients with VA, 40.0% were categorized as area III or IV, compared to 18.7% of the patients with OMI, and 2.9% of the control subjects. 2) Among patients with VA, 64.0% exhibited anxiety states compatible with a psychological disorder. 3) NA and Ad were increased after exercise stress. 4) Serum Mg and Ca were also increased after exposure to exercise stress in all groups, and the degrees of these changes were correlated to the exercise intensity. The %delta Mg/%delta NA ratio, a parameter of the effect of catecholamine on the serum Mg, was greater in patients with VA than in those with OMI and the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of epicardial cyst.

A rare case of epicardial cyst diagnosed at surgery was presented. A 64-year old woman was admitted for evaluation of a mediastinal mass shown by echocardiography to be adjacent to both ventricles. Computed tomography (CT) and magnetic resonance imaging (MRI) studies were performed. On CT, there was evidence of an abnormal mass lesion at the lateral side of the outlet of the right ventricle. The CT number of the mass was 24.7, suggesting cystic lesion. MRI revealed that the intensity of the lesion signal was higher than that of subcutaneous fat on the T2 weighted image. On the T1 weighted image, a low intensity was identified in the same region. During operation a mass originating from the epicardium was diagnosed as an epicardial cyst.

[Alcohol-induced variant angina and considerations of its mechanism: a case report].

A 64-year-old man had episodes of angina pectoris several hours after ingestion of alcohol. Otherwise, anginal attacks never occurred. He was diagnosed as having variant angina based on the typical ST elevation in leads II, III and aVF during the anginal attacks. We performed an alcohol challenge test on his 4th admission day. He was given 540 ml of "sake" at 6:00 p.m. and anginal attacks with ST elevations occurred 9.5 hours after its ingestion. The peak value of plasma ethanol was 136 mg/dl at 9:00 p.m. and it returned to 0 when angina occurred. By alcohol ingestion, urinary excretion of Mg increased in association with a slight decrease in serum Mg. The ratio of serum Ca to Mg was increased from 4.0 at the control state before taking alcohol to 4.5 at the occurrence of anginal attack. Mg content in red blood cells and in plasma catecholamines did not differ between before and after ingesting alcohol. We concluded that the change in the extracellular Ca-Mg equilibrium may contribute to the mechanism of alcohol-induced variant angina.

[Inhibition of vasospastic angina by alcohol ingestion].

A 66-year-old man having a long history of angina on effort has started to show frequent episodes of angina at rest since 6 months ago. He noticed that chest pain was uncommon after taking alcohol. A variant form of angina pectoris (variant angina) was diagnosed by documentation of typical ST elevation during anginal attack and also by inducing coronary arterial spasm with intracoronary administration of ergonovine maleate. Ambulatory ECG monitoring revealed frequent ST elevation during sleep. Since the history suggested that alcohol ingestion could be effective for preventing variant angina, this effect was examined by giving 540 ml of "sake" in the evening. Variant angina was inhibited, while plasma ethanol was detected. The plasma ethanol reached its peak value as 152 mg/dl at 10 o'clock pm and returned to zero after 12 hours. When ethanol disappeared in the plasma, variant angina recurred again. Although the precise mechanism for inhibition of variant angina by alcohol ingestion is not clear, alcohol or its metabolite such as acetaldehyde seems to be able to inhibit coronary arterial spasm.

[Psychological background as a risk factor of variant angina].

In this study, the role of psychological make-up was assessed as a risk factor in the etiology of vasospasm in variant angina (VA) using the Cornell Medical Index (CMI). Study subjects consisted of 15 patients with VA; 32 with effort angina or old myocardial infarction having no vasospasm (EA + OMI); and 34 healthy men. For a neurosis discriminative diagram, the areas I and II were judged as normal and the areas III and IV were judged compatible with a neurotic disorder. Correlation of serum lipid levels with psychological factors was attempted. 1. Among the VA patients, 46.7% belonged to the areas III and IV, as compared to 18% of the patients with EA + OMI, and 2.6% of the healthy subjects. 2. Seventy-three percent of the VA group showed anxiety states indicating a correlation with a psychological disorder. 3. A majority of the VA patients had a variety of psychological symptoms unrelated to myocardial ischemia. 4. Total cholesterol, triglycerides, LDL cholesterol, serum uric acid and the atherogenic index were all lower in the VA group than in the EA + OMI group. 5. In the EA + OMI group, triglycerides, serum uric acid and the atherogenic index were higher in the psychological group than in the non-psychological group. However, total cholesterol, LDL cholesterol and HDL cholesterol were lower in the former than in the latter group. It was concluded that an anxiety state constitutes a contributing background for developing VA and it was speculated that such an anxiety state may lead to an exaggerated secretion of stress hormones, resulting in vasospasm of the coronary arteries.