Simvastatin rescues homocysteine-induced apoptosis of osteocytic MLO-Y4 cells by decreasing the expressions of NADPH oxidase 1 and 2

Takeno, Ayumu; Kanazawa, Ippei; Tanaka, Ken Ichiro; Notsu, Masakazu; Yokomoto‐Umakoshi, Maki; Sugimoto, Toshitsugu

doi:10.1507/endocrj.ej15-0480

Cited by 16 publications

(10 citation statements)

References 34 publications

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“…In bone, the NADPH oxidase Nox4 is a major source of ROS, including H 2 O 2 and superoxide (O ‐ 2 ). It is ubiquitously expressed in many cell types including osteocytes and osteoblasts, and is a constitutively active oxidase . We showed that CSF‐1 decreases Nox4 in cultured normal osteoblasts, suggesting that CSF‐1 protects against oxidative stress .…”

Section: Introductionmentioning

confidence: 77%

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

et al. 2019

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CSF-1 is a key factor in regulating bone remodeling; osteocytes express CSF-1 and its receptor. Viable osteocytes are essential for bone remodeling through cell-cell contact and secretion of factors that regulate osteoblasts and osteoclasts. Increased oxidative stress contributes to osteocyte death and correlates with bone loss during aging. The NADPH oxidase Nox4 is a major source of ROS in bone. CSF-1 decreases Nox4, suggesting that CSF-1 protects against oxidative stress. Here, we show that osteocyte apoptosis previously reported in our global CSF-1KO mice is associated with increased Nox4, as well as 4-HNE expression in osteocytes. Osteocytes isolated from CSF-1KO mice were less viable and showed increased intracellular ROS, elevated NADPH oxidase activity/ Nox4 protein, activation of mTOR/S6K, and downstream apoptosis signals compared with WT osteocytes. Nox4 expression was also increased in CSF-1KO osteocytes and colocalized with MitoTracker Red in mitochondria. Notably, CSF-1 inhibited Nox4 expression and apoptosis cascade signals. In additional studies, shNox4 decreased these signals in CSF-1KO osteocytes, whereas overexpression of Nox4 in WT osteocytes activated the apoptosis pathway. To determine the role of CSF-1 in osteocytes, DMP1Cre-CSF-1cKO (CSF-1cKO) mice that lack CSF-1 in osteocytes/late osteoblasts were developed. Osteocyte defects in CSF-1cKO mice overlapped with those in CSF-1KO mice, including increased apoptosis, Nox4, and 4-HNE-expressing osteocytes. CSF-1cKO mice showed unbalanced cancellous bone remodeling with decreased bone formation and resorption. Continued exposure to high Nox4/ROS levels may further compromise bone formation and predispose to bone loss and skeletal fragility. Taken together, our findings suggest a novel link between CSF-1, Nox4-derived ROS, and osteocyte survival/function that is crucial for osteocyte-mediated bone remodeling. Results reveal new mechanisms by which CSF-1/oxidative stress regulate osteocyte homeostasis, which may lead to therapeutic strategies to improve skeletal health in aging.

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Section: Introductionmentioning

confidence: 77%

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

et al. 2019

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“…2). Moreover, we previously showed that Hcy increased oxidative stress and induced apoptosis of osteocytes by increasing NADPH oxidase 1 (Nox1) and Nox2 expressions [14,35]. These finding suggest that Hcy induces osteoblast dysfunction and AGEs accumulation and increases the apoptosis of osteocyte, resulting in decreased bone formation and bone remodeling as well as increasing AGEs collagen cross-links.…”

Section: Homocysteinementioning

confidence: 90%

Interaction between bone and glucose metabolism [Review]

Kanazawa

2017

Endocr J

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Abstract.Accumulating evidence has shown that bone and glucose metabolism are closely associated with each other. Since the risk of osteoporotic fractures is increased in patients with diabetes mellitus (DM), osteoporosis is recently recognized as one of diabetic complications, called DM-induced bone fragility. Previous studies showed that collagen cross-links of advanced glycation end products (AGEs) and dysfunctions of osteoblast and osteocyte are involved in DMinduced bone fragility. Circulating levels of AGEs and homocysteine are increased in patients with DM, and they directly impair the functions of osteoblast and osteocyte, resulting in decreased bone formation and bone remodeling. On the other hand, bone is recently recognized as an endocrine organ. Previous studies based on in vitro and animal studies showed that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, may regulate glucose homeostasis. Although several clinical studies reported the relationship between osteocalcin and glucose metabolism, further large-scale and intervention studies are necessary to confirm the beneficial effects of osteocalcin on glucose metabolism in human. It has been shown that adenosine monophosphate-activated protein kinase (AMPK), an intracellular energy sensor, is involved in bone metabolism. Adiponectin and metformin stimulate osteocalcin expression and the differentiation of osteoblasts via AMPK activation. Also, AMPK activation protects against oxidative stress-induced apoptosis of osteocytes. These findings suggest that AMPK in osteoblasts and osteocytes may be a therapeutic target for DM-induced bone fragility.

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“…Wassmann et al showed that atorvastatin reduced expression of essential membrane-bound subunits of Nox, p22phox, and Nox1 [39]. Simvastatin has also been shown to inhibit expression of Nox1 and Nox2 genes in osteocytes [40]. Both Rac1 translocation and heme oxygenase 1 (HO-1) upregulation by statins affect Nox inactivation.…”

Section: Signaling Pathways and Molecules Mediating The Effect Of Stamentioning

confidence: 99%

Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

Gorabi

Kiaie

Hajighasemi

et al. 2019

JCM

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In addition to their cholesterol-lowering effects, statins are associated with pleiotropic effects including improvements in heart failure (HF), reduced blood pressure, prevention of the rupture of atherosclerotic plaques and improved angiogenesis. In addition to these cardiovascular benefits, statins have been implicated in the treatment of neurological injuries, cancer, sepsis, and cirrhosis. These cholesterol-independent beneficial effects of statins are predominantly mediated through signaling pathways leading to increased production and bioavailability of nitric oxide (NO). In this review, the mechanistic pathways and therapeutic effects of statin-mediated elevations of NO are described and discussed.

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Simvastatin rescues homocysteine-induced apoptosis of osteocytic MLO-Y4 cells by decreasing the expressions of NADPH oxidase 1 and 2

Cited by 16 publications

References 34 publications

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

Interaction between bone and glucose metabolism [Review]

Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

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