Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway

Yamashita, Misuzu; Otsuka, Fumio; Mukai, Tomoyuki; Otani, Hiroyuki; Inagaki, Kenichi; Miyoshi, Tomoko; Goto, Junko; Yamamura, Masatoshi; Makino, Hírofumi

doi:10.1677/joe-07-0532

Cited by 106 publications

(76 citation statements)

References 65 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Besides regulating bone formation and bone differentiation [113,114], considerable recent data have demonstrated that BMPs are multifunctional regulators in a wide array of biological processes in both vertebrates and invertebrates [115]. In addition to bone, there is evidence that expression of BmP genes is high in the kidney (BMP-3, -4 and -7), lung (BMP-3, -4, -5 and -6), small intestine (BMP-3 and -7), heart (BMP-2, -4, -6 and -7), limb bud (BMP-2, -4, -5 and -7) and teeth (BMP-3, -4 and -7) and that they can regulate the cellular homeostasis by paracrine mechanisms [116].…”

Section: Resultsmentioning

confidence: 99%

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

Otsuka

2010

Endocr J

Self Cite

View full text Add to dashboard Cite

Abstract. Bone morphogenetic proteins (BMPs) were originally identified with regard to their actions to regulate ectopic formation of bone and cartilage and early embryonic development. Subsequently, our research program has investigated a BMP system that exists in the mammalian ovary and plays roles in regulating numerous granulosa cell functions. BMP ligands including BMP-2, -4, -6, -7 and -15 were found to inhibit gondotropin-dependent progesterone synthesis by granulosa cells, which led to the hypothesis that BMPs are a physiological luteinization inhibitor in growing ovarian follicles during the follicular phase of the ovarian cycle. The physiological importance of the BMP system for normal mammalian reproduction has been further recognized by the discovery of aberrant reproductive phenotypes of female sheep and humans having mutated genes encoding BMP-15. Physiological roles of BMPs in the pituitary, hypothalamus, adrenal and other tissues have also been discovered. Here we discuss recent advances in the understanding of autocrine/paracrine actions of BMPs in the systemic regulation of endocrine function.Key words: Bone morphogenetic protein, Folliculogenesis, Ovary, Reproduction, Steroidogenesis Bone morphogenetic proteins (BmPs) were originally isolated from bone tissues as proteins that induce bone and cartilage formation in ectopic extra-skeletal sites in vivo [1]. The amino acid sequences from the corresponding cDNAs revealed that BmP ligands are structurally classified into transforming growth factor (TGF)-β superfamily member. To date, more than 30 members of the TGF-β superfamily have been identified in various species [2,3]. There is no direct evidence that all molecules designated as BMPs can induce cartilage and/or bone formation, whereas it has been well established that BMPs regulate multiple biological processes including cell proliferation, apoptosis, differentiation and morphogenesis. in this review, the recent advances regarding critical BmP actions in the ovarian folliculogenesis, which has been mostly discovered by Shimasaki's laboratory [4,5], and in many of extra-gonadal endocrine tissues are introduced. i) molecular characteristics and receptor signaling of the Bmp systemLigands of the TGF-β superfamily are initially synthesized as large precursor proteins. The precursor proteins dimerize and then are cleaved by proteolytic processing to produce mature dimeric proteins. The BMPs are distinguished from other members by having seven, rather than nine, conserved cysteine residues in the mature region. Six of the seven common cysteines in the mature protein are linked within the subunit to form a rigid structure called a "cysteine knot." The re-

show abstract

Section: Resultsmentioning

confidence: 99%

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

Otsuka

2010

Endocr J

Self Cite

View full text Add to dashboard Cite

show abstract

“…5 can be explained by the well-known pleiotropic effect of the statins already described in other models (20,21,(37)(38)(39). Recent studies have demonstrated that statins may be beneficial in the treatment of T-cellmediated autoimmune diseases (40), due to the involvement of cholesterol in the maintenance of lipid raft structures and its importance in T-cell activation (41).…”

Section: Discussionmentioning

confidence: 99%

“…They are structural analogs of mevalonate that are able to inhibit the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, which is responsible for cholesterol synthesis in mammals. Mainly used in the treatment of hypercholesterolemia, statins are now recognized as immunomodulatory drugs, presenting satisfactory pleiotropic effects in immune disorders (20,21). By reducing cholesterol availability in the intracellular environment, we anticipate a reduction in mycobacterial persistence and multiplication in host cells.…”

Section: T Uberculosis (Tb) and Leprosy Are Chronic Infections Caused Bymentioning

confidence: 99%

Statins Increase Rifampin Mycobactericidal Effect

Lobato

Rosa

Ferreira

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.

show abstract

“…In recent years, statins have been shown to stimulate osteoblast proliferation in vitro, and to promote new bone formation in the skull and os integumentale of newborn rats (13). Statins stimulate increased expression of the BMP-2 gene in osteoblasts, and simvastatin has been suggested to activate the protein kinase pathway and resist the inhibitory action of TNF-α on BMP-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho mitosis (25,26). Statins are associated with a variety of other activities including induction of osteoblast differentiation (27), resistance of the inhibitory effects on osteoblast growth and enhancement of osteoclast activity induced by IL-1, IL-6, TNF-α and other inflammatory factors (28), inhibition of matrix metalloproteinase activity (29), upregulation of vascular endothelial growth factor (VEGF) (30), enhanced activity of endothelial nitric oxide synthase (eNOS) (31) and inhibition of differentiation of adipose cells from multipotential stem cells (32).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Zhao

Zhang

et al. 2011

Mol Med Report

View full text Add to dashboard Cite

Abstract. Apoptosis of osteoblasts has been proposed as the common basis of osteoporosis, with oxidative stress as the major cause. This study was performed to investigate the protective effect of simvastatin (0.001-0.1 µM) on 100 µM hydrogen peroxide (H 2 O 2 )-mediated oxidative stress-induced apoptosis in human osteosarcoma (MG63) cells and the molecular mechanisms involved. Cell apoptosis was evaluated by observation of morphological changes and Annexin V-propidium iodide double staining followed by flow cytometric analysis. MTS assays were used to evaluate cell viability. To investigate the underlying molecular mechanisms, the expression of caspase-3, caspase-9 and Bcl-2 were analyzed by Western blotting. Following stimulation with H 2 O 2 for 24 h, a high proportion of MG63 cells underwent apoptosis, while a dosedependent inhibition of apoptosis was observed in the presence of simvastatin. A significant, dose-dependent reduction in the expression of caspase-3 and caspase-9 protein induced by H 2 O 2 in MG63 cells was observed in response to simvastatin and the Bcl-2 levels were increased. In conclusion, simvastatin protects MG63 cells from oxidative stress-induced apoptosis through downregulation of caspase-3 and caspase-9 activation and upregulation of Bcl-2 expression, suggesting a protective effect in osteoporosis. IntroductionOsteoporosis has been defined as a systemic skeletal disease characterized by gradual loss and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fracture (1). Osteoblasts are responsible for bone formation while osteoclasts are involved in bone resorption. Conditions such as postmenopausal osteoporosis are associated with significant changes in bone turnover; bone formation decreases and bone resorption increases or remains the same, resulting in net bone loss (2,3).Oxidative stress, resulting from excessive levels of reactive oxygen species (ROS), represents a major cause of cellular damage and death in a plethora of pathological conditions, including osteoporosis. This is associated with distinct increases in blood levels of oxidative stress markers (4-6). The main oxygen species responsible for oxidative stress are hydrogen peroxide (H 2 O 2 ), the free radical superoxide anion (O 2 -) and the hydroxyl radical (OH -). Osteoblasts produce antioxidants such as glutathione peroxidase that protect against ROS (7) and osteoclast-generated superoxide contributes to bone degradation (8). In ovariectomized rats, a model of postmenopausal osteoporosis, increased levels of lipid peroxidation and H 2 O 2 and decreased levels of enzymatic antioxidants were detected in tissue homogenates from the femora (9). Furthermore, antioxidant enzyme GPX1 gene polymorphisms are associated with low bone mineral density (BMD) and increased bone turnover markers (10).The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-COA) reductase inhibitor, simvastatin, is a widely used cholesterollowering drug that inhibits hepatic cholesterol biosynthesis. Recent...

show abstract

Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway

Cited by 106 publications

References 65 publications

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

Statins Increase Rifampin Mycobactericidal Effect

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Contact Info

Product

Resources

About