[Association between osteoporosis and atherosclerosis in dyslipidemia.]

Age-related osteoporosis and atherosclerosis is promoted by life style-related diseases such as dyslipidemia and diabetes mellitus. Common factors pathophysiologically involved in both osteoporosis and vascular calcification include senescent cells and osteoprotegerin(OPG). Dyslipidemia may impair both osteoclast and osteoblast function,thereby causing osteoporosis. Statins may have favorable effect on bone. Some anti-osteoporotic medications have also been suggested to show protective effect from atherosclerosis.

[Bone and calcium metabolism associated with malignancy. Malignancy-associated hypercalcemia.]

Hypercalcemia is a poor prognostic factor and can be a direct cause of death in patients with malignancy. Here we provide a brief overview of pathology, etiology and management of malignancy associated hypercalcemia(MAH). MAH can be divided into two categories:humoral hypercalcemia of malignancy(HHM)caused by a systemic soluble factor secreted by the tumor;and local osteolytic hypercalcemia(LOH)in which tumor cells in situ enhance bone resorption. The standard treatment of MAH is intense hydration along with antiresorptive medications such as calcitonin, bisphosphonate and denosumab.

Osteoporosis is highly prevalent in Japanese males with chronic obstructive pulmonary disease and is associated with deteriorated pulmonary function.

Osteoporosis has recently been recognized as a major comorbidity in chronic obstructive pulmonary disease (COPD). We conducted a cross-sectional study in a cohort of 136 Japanese males with COPD to evaluate the prevalence of vertebral fracture (VF) and to explore its relationship with pulmonary function parameters. VFs were present in 108 (79.4%); multiple and severe (SQ grade 2 or 3) VFs were found in 77 (56.6%) and 25 (18.4%), respectively. Multivariate logistic regression analyses revealed that decrease in forced expiratory volume in one second (FEV1.0)/forced vital capacity (FVC) [odds ratio (OR) 0.963, 95% confidence interval (CI) 0.929-998, p = 0.036] was associated with the presence of VF after adjustment for age and that FVC (OR 0.462, 95% CI 0.220-0.968, p = 0.041) and current smoking (OR 2.992, 95% CI 1.128-7.940, p = 0.028) were associated with VF severity (grade 2-3 vs. 1). We also found that FEV1.0 was the sole independent determinant of the number of VFs by stepwise multivariate linear regression (p < 0.001). Bone mineral density (BMD) values were available in 49 subjects. Mean T scores were -2.0 ± 1.2 in femoral neck, -1.4 ± 1.2 in total hip and -1.1 ± 1.4 in lumbar spine. Nineteen patients (38.8%) had a BMD T score less than -2.5. BMD Z scores of all the sites showed a progressive decrease as GOLD stage of COPD advanced (p < 0.05). Our results indicate a high prevalence of osteoporosis in Japanese male COPD patients and a strong inter-relationship between the two diseases, re-emphasizing the urgent need for appropriate intervention to maintain both bone and lung health.

[Anti-Dickkopf1 (Dkk1) antibody as a bone anabolic agent for the treatment of osteoporosis].

Wnt/ß-catenin signaling pathway plays an important role in bone metabolism. This signal is subject to strict regulation, involving endogenous soluble inhibitors. Dkk1 is a member of family of secreted protein which functions in head induction during Xenopus embryogenesis. Dkk1 forms a ternary complex with LRP5/6 and Kremen, resulting in suppression of Wnt signaling and decreased bone formation. Heterozygous knockout mice of Dkk1 show high bone mass, while transgenic mice overexpressing Dkk1 exhibit low bone mass phenotype. Anti-Dkk1 monoclonal antibody has been shown to accelerate bone formation and increase bone mineral density in various animal models and is under development as a bone-anabolic agent.

[Treatment of malignancy associated hypercalcemia].

Malignancy associated hypercalcemia (MAH) is a paraneoplastic syndrome that impairs the quality of life and that can be a direct cause of death. MAH is classified into two major categories : humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (LOH) . Bisphosphonates are the gold standard of treatment for MAH, because enhanced resorption causing a massive calcium mobilization from bone plays a central role in the pathogenesis of MAH. Calcitonin can be used initially as an adjunctive therapy, because it takes a few days for bisphosphonates to be effective. Saline infusion is also necessary to improve dehydration and renal insufficiency inevitably accompanying MAH.

Cytosolic phospholipase A2 alpha inhibitor, pyrroxyphene, displays anti-arthritic and anti-bone destructive action in a murine arthritis model.

OBJECTIVE: The aim of this study is to verify the crucial role of cytosolic phospholipase A2 alpha (cPLA2 alpha) in the pathogenesis of collagen-induced arthritis in mice and to determine the anti-arthritic effects of pyrroxyphene, a cPLA2 alpha inhibitor. METHODS: Pyrroxyphene was administered (p.o.) twice a day for 18 days at 30 and 100 mg/kg. Its effects on arthritic symptoms, bone destruction, cPLA2 alpha activity, levels of prostaglandin E(2) and leukotriene B(4), and mRNA expression of matrix metalloproteinase (MMP)-3, -8, -9, -13 and cyclooxygenase-2 (COX-2) were tested. RESULTS: cPLA2 alpha activity gradually increased and showed a correlation with the severity of arthritis. Pyrroxyphene strongly inhibited the incidence of arthritis and bone destruction. Moreover, it significantly inhibited both the increase in levels of cPLA2 alpha and eicosanoids as well as the mRNA expression of MMP-3, -8, -9, -13, and COX-2. CONCLUSION: These results demonstrate that cPLA2 alpha plays an important role in the pathogenesis of collagen-induced arthritis. Oral administration of pyrroxyphene achieved anti-arthritic activity through inhibition of cPLA2 alpha activity, which led to a reduction in eicosanoid levels and suppression of MMP and COX-2 mRNA expression. These results support a potential therapeutic role for cPLA2 alpha inhibitors in the treatment of human rheumatoid arthritis.

A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations.

BACKGROUND: Retinoic acid receptor-related orphan receptor gamma t (RORγt) has critical roles in the development, maintenance and function of interleukin (IL)-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune disease, particularly psoriasis. On the other hand, RORγt is also critical for controlling apoptosis during thymopoiesis, and genetic RORγt ablation or systematic RORγt inhibition cause progressive thymic aberrations leading to T cell lymphomas. OBJECTIVE: We investigated whether topical administration of our novel RORγt inhibitor, S18-000003 has therapeutic potential for psoriasis with low risk of thymic aberrations. METHODS: We evaluated the effect of topical S18-000003 on psoriasis-like skin inflammation and influence on the thymus in a 12-O-tetradecanoylphorbol-13-acetate-induced K14.Stat3C mouse psoriasis model. RESULTS: S18-000003 markedly inhibited the development of psoriatic skin inflammation via suppression of the IL-17 pathway. In the skin, S18-000003 suppressed all subsets of IL-17-producing cells that we previously identified in this psoriasis model: Th17 cells, Tc17 cells, dermal γδ T cells, TCR- cells that probably included innate lymphoid cells, and CD4-CD8- double-negative αß T cells. Notably, neither reduction of CD4+CD8+ double-positive thymocytes nor dysregulation of cell cycling was observed in S18-000003-treated mice, even at a high dose. CONCLUSION: Our topically administered RORγt inhibitor is a potential therapeutic agent for psoriasis with low risk of thymic lymphoma.

[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes].

We examined the behavioral pharmacological properties of six benzodiazepine (omega) receptor ligands including brotizoram, nitrazepam, quazepam, rilmazafone, zolpidem and zopiclone and the binding of these drugs with omega receptor subtypes. Behavioral tests were performed at the time of the maximal effects induced by each drug following its oral administration to mice. All of these drugs dose-dependently induced impairment of motor coordination as rotarod performance and potentiation of thiopental-induced anesthesia as hypnotic effect. The hypnotic effects of rilmazafone, whose major metabolites were bound to both omega1 and omega2 receptors with high affinity, and omega1 selective quazepam were about 20 times more effective than the induction of motor impairments when compared with ED50 values. However, there was no difference between the ED50 values of omega1 selective zolpidem alone in these two tests. An antianxiety efficacy of zolpidem was relatively weak unlike that of other drugs in the elevated plus-maze. It has been reported that omega2, but not omega1, receptors are associated with motor impairment and anxiolytic effect. The weak anxiolytic effect of zolpidem supports the previous hypothesis. However, the strong motor incoordination of zolpidem suggests that not only omega2 but also omega1 receptors are related to motor impairment unlike the previous hypothesis.

The role of histamine H(1) receptors in late-phase reaction of allergic conjunctivitis.

The role of histamine H(1) receptors in the late-phase reaction of allergic conjunctivitis was studied using histamine H(1) receptor-deficient mice. To clarify the eosinophil infiltration, which is a reliable indicator of late-phase reaction, eosinophil peroxidase activity in the conjunctiva was measured. Mice were actively immunized with ovalbumin, and conjunctivitis was induced by topical instillation of ovalbumin. A significantly high eosinophil peroxidase level in the conjunctiva was observed in sensitized wild-type mice, whereas sensitized histamine H(1) receptor-deficient mice showed no significant increase in the conjunctival eosinophil peroxidase level. In addition, the elevation of eosinophil peroxidase level observed in sensitized wild-type mice was significantly antagonized by pretreatment with anti-P-selectin antibody. From these findings, it was concluded that eosinophil infiltration into the conjunctival tissue in late-phase reaction of allergic conjunctivitis is mediated by P-selectin stored in endothelial cells via histamine H(1) receptors.

Inhibitory effects of glucocorticoids on rat eosinophil superoxide generation and chemotaxis.

Eosinophil infiltration into inflammatory tissues and the subsequent release of inflammatory mediators are the hallmarks of several inflammatory allergic diseases. Although there have been a considerable number of publications on anti-inflammatory effects of glucocorticoids, little is known about whether glucocorticoids affect the activation of eosinophils directly. We studied the effects of three glucocorticoids, mometasone furoate, dexamethasone and beclomethasone dipropionate, on superoxide generation and the chemotaxis of rat eosinophils. Highly purified rat eosinophils were treated for 6 h with mometasone furoate, dexamethasone or beclomethasone dipropionate. Eosinophils were stimulated with phorbol myristate acetate (PMA) for superoxide generation, while for induction of chemotaxis, platelet-activating factor (PAF) or leukotriene B(4) (LTB(4)) was used. None of the glucocorticoids used in the present study caused significant suppressive effects on superoxide generation induced by PMA. On the other hand, both PAF- and LTB(4)-induced migration of rat eosinophils were inhibited in a concentration-dependent manner by glucocorticoids. Mometasone furoate showed a significant effect at concentrations higher than 10(-11) M. Dexamethasone and beclomethasone dipropionate also caused a significant inhibition at concentrations higher than 10(-8) and 10(-7) M, respectively. These results indicated that the anti-inflammatory effects of glucocorticoids were mediated by direct inhibition of eosinophil migration. Furthermore, mometasone furoate was suggested to be more useful than the other drugs in the treatment of allergic diseases responsible for eosinophil chemotaxis.