No abstract

Risedronate, a nitrogen-containing bisphosphonate, is widely used in the clinical field for the treatment of osteoporosis. Risedronate is known to exert its effects through binding to hydroxyapatite in bone tissue, inhibiting osteoclastic activity, and inducing apoptosis of osteoclasts. The purpose of this study was to determine the effects of risedronate on osteoclast differentiation in vitro and on an inflammatory bone loss model in vivo. Risedronate inhibited osteoclast differentiation in co-culture of bone marrow cells (BMCs) and osteoblasts, and suppressed receptor activator of nuclear factor (NF)-k kB ligand (RANKL)-mediated osteoclast differentiation from bone marrow-derived macrophages (BMMs) in a dose-dependent manner without toxicity. Risedronate significantly inhibited expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 induced by RANKL. To examine the effect of risedronate on bone loss in vivo, we used a mouse model of lipopolysaccharide (LPS)-mediated bone loss. Micro-CT analysis of the femurs showed that LPS treatment caused bone loss. However, bone loss was significantly attenuated in mice administered with risedronate. Taken together, we conclude that risedronate exerts beneficial effects on osteoporosis by inhibiting osteoclast differentiation both directly and indirectly. In infectious conditions, the inhibitory effect of risedronate on bone erosion was excellent. Thus risedronate could be a treatment option for osteoporosis caused by inflammatory and infectious conditions.

Hypothyroidism has various cardiovascular manifestation and exhibits electrocardiographic change. The QT dispersion on surface ECG reflects regional variations in myocardial repolarization. The effect of L-thyroxine treatment on ECG parameters, such as QT dispersion, in patients with primary hypothyroidism were investigated. This study involved 18 patients (3 men, 15 women, ages: 48±18 yr) with primary hypothyroidism. All patients were checked with a standard 12-lead ECG before and after L-thyroxine treatment. Various ECG parameters were then measured twice. The mean L-thyroxine treatment duration was 22±2.7 months. The mean thyroid-stimulating hormone levels of patients before and after therapy were 40.2±29.8 µU/mL, 3.6±4.6 µU/mL (p<0.001) and free-T4 levels were 0.44±0.38 ng/dL, 1.51±0.39 ng/dL (p<0.001). After L-thyroxine treatment, QT interval (395±42 vs. 380±24 msec, p<0.05), QTc interval (434±32 vs. 417±23 msec, p<0.05), QT dispersion (45±23 vs. 30±13 msec, p=0.008), QTc dispersion (49±23 vs. 32±14 msec, p=0.005) significantly decreased. There were no significant changes in the PR and RR intervals, as well as the QRS duration. Our findings suggest that the thyroid hormone affects ventricular inhomogenicity, and that L-thyroxine replacement therapy may reduce malignant ventricular arrhythmia and sudden cardiac death in primary hypothyroidism.

It has been reported that Janus tyrosine kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of numerous malignancies and immune reactions, and inhibition of JAK has been implicated in cell growth inhibition. The role which JAK has on osteoclast differentiation and anti-bone resorptive activity is not well understood. In this study, we investigated the effects of a pan-JAK inhibitor, pyridone 6, on osteoclast differentiation and bone-resorption in vitro and ex vivo. Pyridone 6 inhibited osteoclast differentiation in mouse bone marrow macrophage (BMM) cultures stimulated by the receptor activator of nuclear factor-k kB (NF-k kB) ligand (RANKL) and co-cultures of bone marrow cells and osteoblasts. Pyridone 6 suppressed the expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 in BMMs. It also inhibited the bone resorptive activity of mature osteoclasts that was accompanied by disruption of actin rings. Pyridone 6 also suppressed I-k kB degradation and extracellular signal-regulated kinase (ERK) in mature osteoclasts, suggesting that these are the key molecules that pyridone 6 targets in the inhibition of osteoclast function. These results demonstrate inhibition of JAK may be useful for the treatment of bone-resorptive diseases, such as osteoporosis.

Background: Bilirubin prevents oxidative modification of low density lipoprotein, and may protect vessels from atherosclerosis. Several studies showed an inverse relationship between serum bilirubin and coronary artery disease. However, there are some needs to clarify the relationship between serum bilirubin and carotid atherosclerosis in type 2 diabetes, especially. Methods: A total of 346 type 2 diabetic patients, between 35 and 95 years of age (146 men and 200 women), were studied. Subjects with normal serum total bilirubin were divided into two groups, according to their serum total bilirubin levels (group I, total bilirubin ≥ 1.0 mg/dL [n = 59]; group II, total bilirubin ≤ 0.5 mg/dL [n = 76]). Carotid intima-media thickness (IMT) and plaque scores were measured by ultrasonography. Carotid atherosclerosis was defined by the presence of plaque or more than 1 mm of common carotid IMT. Results: Carotid IMT was positively correlated with age, duration of diabetes and hypertension, high sensitive C-reactive protein (hs-CRP) and fibrinogen, but, it was negatively correlated with bilirubin, gamma glutaryltransferase, albumin, hemoglobin, cystatin C and estimated-glomerular filtration rate (GFR) in all subjects. After controlling for sex, age and levels of hemoglobin, direct bilirubin only was negatively correlated with carotid IMT (r = -0.151, P = 0.034). Low serum total bilirubin group had a lot of female, long duration of diabetes and hypertension, higher hs-CRP, platelet counts, serum creatinine, HbA1c and homeostasis model assessmentinsulin resistance, lower albumin, hemoglobin, estimated-GFR and quantitative insulin sensitivity check index. Carotid IMT and plaque scores were significantly greater in low serum bilirubin group (0.785 ± 0.210 mm vs. 0.678 ± 0.146 mm, P < 0.01; 1.95 ± 2.56 vs. 1.03 ± 1.40, P < 0.05, respectively) than in the high serum bilirubin group. Multivariate logistic regression analysis showed that age, serum albumin and total bilirubin were independent associated factors for carotid atherosclerosis in type 2 diabetic women. Conclusion: Total bilirubin is inversely correlated with carotid atherosclerosis in type 2 diabetic patients, and it is an independent associated factor for carotid atherosclerosis in women. (Endocrinol Metab 27:126-131, 2012)