Takahisa Tanikawa

Advanced Glycation End Products Induce Calcification of Vascular Smooth Muscle Cells through RAGE/p38 MAPK

Background: Mönckeberg’s calcification in diabetes, known as medial artery calcification, is an independent predictor of cardiovascular mortality. However, the mechanism underlying this phenomenon remains to be elucidated. We demonstrate that advanced glycation end products (AGEs) induce calcification of vascular smooth muscle cells through the receptor for AGE (RAGE)/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Methods: We detected vascular calcification by von Kossa staining. Alkaline phosphatase (ALP) activity was determined by measuring p-nitrophenol. Osteocalcin concentrations were measured using ELISA. Western blotting for protein phosphorylation and real-time RT-PCR for expression of mRNA were used. Results: AGEs induced calcification of vascular smooth muscle cells. AGEs also induced the expression of Runx2 mRNA. In addition, AGEs increased ALP activity and osteocalcin secretion. Furthermore, AGEs induced phosphorylation of p38 MAPK, and this phosphorylation was inhibited by the anti-RAGE blocking antibody. Increased ALP activity was inhibited by the p38 MAPK inhibitor or anti-RAGE blocking antibody. Furthermore, the p38 MAPK inhibitor and anti-RAGE blocking antibody both inhibited AGE-induced calcification of vascular smooth muscle cells. Diabetic serum induced calcification of smooth muscle cells and the calcification was inhibited by RAGE blocking. Conclusion: Our findings indicate that AGEs induce calcification of vascular smooth muscle cells by osteoblast-like differentiation of smooth muscle cells through RAGE/p38 MAPK.

Advanced glycation end products increase endothelial permeability through the RAGE/Rho signaling pathway

MINT‐7301204, MINT‐7301186: RhoA (uniprotkb:P61586) physically interacts (MI:0915) with RAGE (uniprotkb:Q15109) by anti bait coimmunoprecipitation (MI:0006)

Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway

Galectin-9 is a beta-galactoside-binding lectin expressed in various tissues. It binds various glycoconjugates and modulates a variety of biological functions in various cell types. Although galectin-9 is expressed in bone, its function in human osteoblasts remains unclear. We demonstrate that galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway in the absence of bone morphogenetic proteins (BMPs). Galectin-9 increases alkaline phosphatase activities in human osteoblasts and induces the phosphorylation of Smad1/5/8 and translocation of Smad4 to the nucleus in the absence of BMPs. Galectin-9 also induces binding of Smad4 to the Id1 promoter and increases its activity. Anti-CD44 antibody inhibits Smad1/5/8 phosphorylation by galectin-9. Galectin-9 binds to CD44 and induces the formation of a CD44/BMP receptor complex. Because Smad1 is phosphorylated by BMP receptors, we propose that formation of the CD44/BMP receptor complex induced by galectin-9 may provide a trigger for the activation of Smads.

Interaction of Galectin-9 With Lipid Rafts Induces Osteoblast Proliferation Through the c-Src/ERK Signaling Pathway†‡

Galectin‐9 is a β‐galactoside‐binding lectin expressed in various tissues, including bone. The role of galectin‐9 in human osteoblasts, however, remains unclear. This study showed that galectin‐9 interacts with lipid rafts and induces osteoblast proliferation through the c‐Src/ERK signaling pathway.

Severe hypercalcemia and hypernatremia associated with calcipotriol for treatment of psoriasis

150cm; weight, 61.7 kg). Based on the presence of cardiomegaly on the chest radiogram, she was treated with diuretics (furosemide) by the dermatologists, in addition to water restriction. Psoriasis was known to be refractory to therapy, and treatment with calcipotriol (active form of vitamin D3 analogue, 50 μg/gm) ointment at a dose of 90g/week commenced on April 3, 2002. Anorexia started to appear at 19 days after initiation of calcipotriol treatment. After a couple of days, oliguria and clouding of consciousness developed. On April 22, serum calcium and sodium levels were elevated at 14.0mg/dl and 171mEq/ l, respectively. Unfortunately, serum parathyroid hormone was not measured at that time. Furthermore, she developed acute renal failure (blood urea nitrogen was elevated from 12 to 45mg/dl and serum creatinine increased from 0.7 to 2.3mg/dl). Consultation with our department was made on April 23, 2002. Physical examination at that time showed body weight of 46.2kg (body weight loss was 15.5kg from admission) and low blood pressure (98/50mmHg). Consciousness level was graded as cloudy (Glasgow Coma Scale 7). The greater part of her body was covered with psoriasis. Palpebral conjunctiva was slightly anemic, and oral mucosa was very dry. Laboratory studies (Table 1) showed proteinuria and urinary specific gravity of 1.019. Blood cell counts showed leukocytosis and slight anemia, but hematocrit tended to be high (45.4%), indicating severe dehydration. Serum Na, Cl, and Ca concentrations were elevated, as was urinary calcium concentration. Serum 1,25(OH)2D was also elevated (94.4 pg/ml), and renal impairment was recognized (Ccr 42.9ml/min). Based on these clinical features and laboratory findings, we discontinued treatment with calcipotriol and calcium lactate, and instead immediate measures were taken to ensure rehydration by intravenous saline and administration of bisphosphonates to reduce serum calcium concentration. Fortunately, she showed recovery Introduction

Cardiac Autonomic Balance and QT Dispersion During Head‐Up Tilt Testing in Diabetics with and without Sensory Neuropathy

Background Cardiovascular autonomic dysfunction is associated with higher mortality in diabetics. However, detection methods of early cardiac diabetic dysautonomia, and its correlation with severity of sensory neuropathy, have not been described. Methods We analyzed the heart rate variability (HRV) by spectral analysis and QT dispersion in 23 diabetics with and without sensory neuropathy, and in 5 age‐matched controls, in the supine position and during head‐up tilt testing (HUT). Diabetics were divided into 3 groups according to the degree of sensory neuropathy. Results In the spectral analysis of HRV, the high frequency components in the supine position decreased as a function of severity of the neuropathy. High frequency in diabetics was significantly decreased in the supine position, even in absence of sensory neuropathy. The low/high frequency ratio (L/H) in the supine position was similar among controls and the 3 patient groups. L/H in diabetics with moderate or severe neuropathy did not increase from the supine to the upright position. Baseline QT dispersion increased proportionally to the severity of sensory neuropathy and, in patients without apparent sensory neuropathy, QT dispersion increased significantly during HUT. Conclusions The spectral analysis of HRV and measurements of QT dispersion, before and during HUT, were reliable detection methods of early abnormalities in autonomic balance and may predict a risk of sudden cardiac death in diabetics.

Adult-onset idiopathic progressive acro-osteolysis with proximal symphalangism.

We experienced a 57‐year‐old female with adult‐onset non‐congenital idiopathic acro‐osteolysis combined with proximal symphalangism. At the age of 36, she developed severe pain and swelling of the toe base of both feet and underwent Clayton surgery. However, the size of her toes diminished progressively over the 5‐year period after surgery. At the age of 41, she suffered pain and swelling of the proximal interphalangeal (PIP) joints of fingers of both hands. These PIP joints became rigid and inflexible. Subsequently, she noticed shortening of the little finger of both hands, followed later by shortening of the index, middle, and ring fingers. At the age of 57, the thumbs began to shorten. Laboratory and endocrinological examinations were not abnormal. Finally, we diagnosed her with acro‐osteolysis combined with proximal symphalangism by radiological examination. In this case, previously unreported mutations of the Noggin gene were identified. This is the first case report of adult‐onset, non‐congenital idiopathic acro‐osteolysis combined with proximal symphalangism.