The BMP signaling and in vivo bone formation

Cao, Xu; Chen, Di

doi:10.1016/j.gene.2005.06.017

Cited by 274 publications

(206 citation statements)

References 92 publications

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“…Signaling through BMP is regulated extracellularly by antagonists such as noggin and chordin (De Robertis and Kuroda 2004), and intracellularly by the Smad family of signaling proteins that act downstream from specific BMP receptors (Cao and Chen 2005). BMPs are strong candidate genes for regulation of bone mass, and naturally occurring mutations in various components of the BMP pathway result in defects of limb formation (Seemann et al 2005).…”

Section: Bone Morphogenic Proteins (Bmps)mentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

291

229

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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Section: Bone Morphogenic Proteins (Bmps)mentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

291

229

View full text Add to dashboard Cite

show abstract

“…(8)(9)(10) RUNX2 is the obligate OB transcription factor that regulates, and is in turn regulated by, a number of factors to control the expression of genes involved in OB differentiation and function. Platelet-derived growth factor (PDGF) is a potent MSC mitogen that plays an important role in OB proliferation and differentiation, with the addition of PDGF to osteogenic MSC cultures strongly inhibiting OB differentiation and function in vitro.…”

Section: Introductionmentioning

confidence: 99%

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

Martin¹,

Fitter²,

Bong³

et al. 2010

Journal of Bone and Mineral Research

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Osteoblasts are bone-forming cells derived from mesenchymal stromal cells (MSCs) that reside within the bone marrow. In response to a variety of factors, MSCs proliferate and differentiate into mature, functional osteoblasts. Several studies have shown previously that suppression of the PI3K and mTOR signaling pathways in these cells strongly promotes osteogenic differentiation, which suggests that inhibitors of these pathways may be useful as anabolic bone agents. In this study we examined the effect of BEZ235, a newly developed dual PI3K and mTOR inhibitor currently in phase I-II clinical trials for advanced solid tumors, on osteogenic differentiation and function using primary MSC cultures. Under osteoinductive conditions, BEZ235 strongly promotes osteogenic differentiation, as evidenced by an increase in mineralized matrix production, an upregulation of genes involved in osteogenesis, including bone morphogenetic proteins (BMP2, -4, and -6) and transforming growth factor b1 (TGF-b1) superfamily members (TGFB1, TGFB2, and INHBE), and increased activation of SMAD signaling molecules. In addition, BEZ235 enhances de novo bone formation in calvarial organotypic cultures. Using pharmacologic inhibitors to delineate mechanism, our studies reveal that suppression of mTOR and, to a much lesser extent PI3K p110a, mediates the osteogenic effects of BEZ235. As confirmation, shRNA-mediated knockdown of mTOR enhances osteogenic differentiation and function in SAOS-2 osteoblast-like cells. Taken together, our findings suggest that BEZ235 may be useful in treating PI3K/mTOR-dependent tumors associated with bone loss, such as the hematologic malignancy multiple myeloma. ß

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“…One family of proteins thought to play an important role of vascular development and remodeling is the TGF-β superfamily of signaling molecules. The bone morphogenetic proteins (BMPs) are the largest subgroup of the transforming growth factor beta (TGF-β) protein superfamily, and over 20 BMP subfamily members have been identified in human and mouse [2]. Although they were named for their ability to induce ectopic cartilage and bone formation in vivo [3], these proteins have subsequently been shown to play key regulatory roles in a diverse set of developmental processes [4].…”

mentioning

confidence: 99%

Endothelial Bmp4 Is Induced During Arterial Remodeling: Effects on Smooth Muscle Cell Migration and Proliferation

Corriere

Rogers

Eliason

et al. 2008

Journal of Surgical Research

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Background-Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of proteins that have multiple functional roles in mammalian development. A role for BMP4 in adult vascular remodeling has recently been suggested. We evaluated the expression of Bmp4 during neointimal lesion development in vivo. We then assessed the role BMP4 signaling on SMC function during neointimal lesion development.

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The BMP signaling and in vivo bone formation

Cited by 274 publications

References 92 publications

Genetic regulation of bone mass and susceptibility to osteoporosis

Genetic regulation of bone mass and susceptibility to osteoporosis

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

Endothelial Bmp4 Is Induced During Arterial Remodeling: Effects on Smooth Muscle Cell Migration and Proliferation

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