The role of adipokines in bone homeostasis

Growing evidence has shown that adipose tissue accumulation is associated with bone metabolism. Arguably, adipokines, secretory proteins of adipose tissue, are involved in bone homeostasis including development and remodeling. The "classical" adipokine leptin regulates bone formation negatively and bone resorption positively via central nervous system. Leptin also stimulates directly osteoblastogenesis and inhibits osteoclastogenesis through stimulation of osteoprotegerin and inhibition of receptor activator for nuclear factor κB ligand (RANKL) expression in osteoblasts. Another major adipokine, adiponectin, and its receptor are expressed in osteoblasts. Adiponectin stimulates the proliferation, differentiation, and mineralization of osteoblastic cells, and indirectly stimulates osteoclast differentiation via enhancement of RANKL and inhibition of osteoprotegerin expression in osteoblasts, whereas directly inhibits osteoclast activity and bone resorption. Altogether, adipose tissue via adipokines plays a crucial role in the maintenance of bone homeostasis. These findings are reviewed herein.Adipobiology 2011; 3: 39-50

Adiponectin and AMP kinase activator stimulate proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells

<p>Abstract</p> <p>Background</p> <p>Adiponectin is a key mediator of the metabolic syndrome that is caused by visceral fat accumulation. Adiponectin and its receptors are known to be expressed in osteoblasts, but their actions with regard to bone metabolism are still unclear. In this study, we investigated the effects of adiponectin on the proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells.</p> <p>Results</p> <p>Adiponectin receptor type 1 (AdipoR1) mRNA was detected in the cells by RT-PCR. The adenosine monophosphate-activated protein kinase (AMP kinase) was phosphorylated by both adiponectin and a pharmacological AMP kinase activator, 5-amino-imidazole-4-carboxamide-riboside (AICAR), in the cells. AdipoR1 small interfering RNA (siRNA) transfection potently knocked down the receptor mRNA, and the effect of this knockdown persisted for as long as 10 days after the transfection. The transfected cells showed decreased expressions of type I collagen and osteocalcin mRNA, as determined by real-time PCR, and reduced ALP activity and mineralization, as determined by von Kossa and Alizarin red stainings. In contrast, AMP kinase activation by AICAR (0.01–0.5 mM) in wild-type MC3T3-E1 cells augmented their proliferation, differentiation, and mineralization. BrdU assay showed that the addition of adiponectin (0.01–1.0 μg/ml) also promoted their proliferation. Osterix, but not Runx-2, appeared to be involved in these processes because AdipoR1 siRNA transfection and AICAR treatments suppressed and enhanced osterix mRNA expression, respectively.</p> <p>Conclusion</p> <p>Taken together, this study suggests that adiponectin stimulates the proliferation, differentiation, and mineralization of osteoblasts via the AdipoR1 and AMP kinase signaling pathways in autocrine and/or paracrine fashions.</p

Prehypertension increases the risk of atherosclerosis in drug-naïve Japanese patients with type 2 diabetes mellitus.

PURPOSE:Hypertension is a risk factor of atherosclerotic diseases. However, the importance of prehypertension in Japanese patients with type 2 diabetes mellitus (T2DM) is controversial. The aim of this study was to examine association between prehypertension, hypertension and atherosclerosis in T2DM. METHODS:We recruited 179 Japanese patients with T2DM, who never took any medication for diabetes, hypertension, dyslipidemia, or atherosclerosis. Intima-media thickness (IMT) of common carotid artery was evaluated by high-resolution B-mode ultrasonography. RESULTS:Multiple regression analysis adjusted for age, duration of diabetes, body mass index, HbA1c, fasting C-peptide, triglyceride, HDL-cholesterol, LDL-cholesterol, and estimated glomerular filtration rate showed that systolic blood pressure (SBP), but not diastolic BP, was significantly and positively associated with maximum IMT (IMT-max), mean IMT, and plaque score (β = 0.28, p140 mmHg). Multiple logistic regression analysis adjusted for the variables described above plus gender and smoking showed that prehypertension and hypertension were significantly associated with the increased risk of atherosclerosis [prehypertension; odds ratio (OR) 3.45, 95% confidence interval (CI) 1.11-10.76, p = 0.033, and hypertension; OR 7.29, 95%CI 1.99-26.78, p = 0.003]. CONCLUSION:These findings suggest that prehypertension categorized by SBP is an important risk factor of atherosclerosis independently of conventional risk factors in patients with T2DM

Nerve conduction velocity is negatively associated with intima-media thickness and brachial-ankle pulse wave velocity in men with type 2 diabetes mellitus.

OBJECTIVE:Previous studies suggest that the presence of diabetic peripheral polyneuropathy (DPN) is associated with atherosclerotic diseases; however, little is known about the relationship between diabetic nerve conduction velocity (NCV) versus arterial stiffness and atherosclerosis parameters. METHODS:The subjects in this study were 292 men with type 2 diabetes mellitus (T2DM). All subjects underwent NCV examination at median and tibial nerves as motor nerve (MCV) as well as median and sural nerves as sensory nerve (SCV). Brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (IMT) were evaluated as arterial stiffness and atherosclerosis parameters. RESULTS:Pearson's correlation coefficient showed that NCV at all sites negatively correlated with baPWV, maximal and mean IMT (IMT-Max and IMT-Mean), and plaque score (all p values p<0.01 at least). Multiple regression analyses adjusted for confounding factors such as age, duration of diabetes, body mass index, HbA1c, fasting C-peptide, systolic blood pressure, HDL-cholesterol, LDL-cholesterol and albuminuria showed that the association of NCV with IMT-Max, ITM-Mean, and plaque score remained significant (all p values p<0.05 at least) except that between SCV at median and IMT-Max. Moreover, SCV at median (forearm) and sural were significantly associated with baPWV (p = 0.023 and p = 0.027, respectively). CONCLUSION:The present study showed that DPN estimated by quantitative NCV is linearly associated with the deterioration of arterial stiffness and atherosclerosis parameters in T2DM independently of various diabetic and atherosclerotic factors

Albuminuria Increases All-Cause Mortality in Japanese Patients with Type 2 Diabetes Mellitus

Previous studies have reported that diabetic kidney disease is associated with cardiovascular events and death. Little is known about the independent association of albuminuria and estimated glomerular filtration rate (eGFR), with mortality in Asian patients with type 2 diabetes mellitus (T2DM) without renal failure. We conducted a historical cohort study to clarify this issue in Japanese patients with T2DM. In this study, we recruited 385 patients with T2DM, who never had chronic renal failure (eGFR &lt; 30 mL/min/1.73 m2 at baseline) and malignant diseases. With the end point of all-cause mortality, Cox regression analysis was performed. During the observational period of 7 years, 54 patients died. Cox regression analysis adjusted for confounding factors such as age, duration of diabetes, body mass index, and HbA1c, and showed that urinary albumin level was significantly associated with the mortality [hazard ratio (HR) = 1.32, 95% confidence interval (CI) = 1.03&ndash;1.70 per standard deviation (SD) increase, p = 0.031]. After additional adjustment for eGFR, the association remained significant (HR = 1.32, 95% CI = 1.02&ndash;1.70 per SD increase, p = 0.033). On the other hand, eGFR was not associated with the mortality. The present study showed that higher urinary albumin was associated with increased all-cause mortality in T2DM, independently of eGFR. These findings suggest that, regardless of eGFR, albuminuria is important for the increased risk of mortality in Japanese T2DM patients without chronic renal failure (eGFR &lt; 30 mL/min/1.73 m2). However, because of several limitations, further large-scale longitudinal studies are necessary to confirm the present study

Background characteristics of subjects.

<p>Background characteristics of subjects.</p

Comparison of various variables among subjects with normotension, prehypertension, and hypertension.

<p>Comparison of various variables among subjects with normotension, prehypertension, and hypertension.</p