The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Bram C J Van Der Eerden - One of the best experts on this subject based on the ideXlab platform.

  • Age-Related Skeletal Dynamics and Decrease in Bone Strength in DNA Repair Deficient Male Trichothiodystrophy Mice
    2016
    Co-Authors: Claudia Nicolaije, Matthias Priemel, Karin E M Diderich, S M Botter, J H Waarsing, J S Day, Arndt F Schilling, Harrie Weinans, Bram C J Van Der Eerden
    Abstract:

    Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for Skeletal Homeostasis with age and support the idea that accumulation of damage interferes with normal Skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structur

  • age related Skeletal dynamics and decrease in bone strength in dna repair deficient male trichothiodystrophy mice
    PLOS ONE, 2012
    Co-Authors: Claudia Nicolaije, Matthias Priemel, Karin E M Diderich, S M Botter, J H Waarsing, J S Day, Renata M C Brandt, Arndt F Schilling, Harrie Weinans, Bram C J Van Der Eerden
    Abstract:

    Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for Skeletal Homeostasis with age and support the idea that accumulation of damage interferes with normal Skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength.

Ulf H Lerner - One of the best experts on this subject based on the ideXlab platform.

  • a new wnt on the bone wnt16 cortical bone thickness porosity and fractures
    bonekey Reports, 2015
    Co-Authors: Francesca Gori, Ulf H Lerner, Claes Ohlsson, Roland Baron
    Abstract:

    The last decade has provided abundant data implicating the WNT pathway in bone development and in the regulation of Skeletal Homeostasis. Rare human mutations together with gain- and loss-of-function approaches in mice have clearly demonstrated that disrupted regulation of this pathway leads to altered bone mass. In addition to these rare human and mice mutations, large population-based genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in ∼60 loci strongly associated with variations in bone mineral density (BMD) at different Skeletal sites. Among the loci/genes identified by BMD GWAS, components of the WNT signaling pathway are numerous and have been shown to contribute to Skeletal development and Homeostasis. Within the components of WNT signaling, the gene coding for WNT16, one of the 19 WNT ligands of the human genome, has been found strongly associated with specific bone traits such as cortical bone thickness, cortical porosity and fracture risk. Recently, the first functional characterization of Wnt16 has confirmed the critical role of Wnt16 in the regulation of cortical bone mass and bone strength in mice. These reports have extended our understanding of Wnt16 function in bone Homeostasis and have not only confirmed the unique association of Wnt16 with cortical bone and fracture susceptibility, as suggested by GWAS in human populations, but have also provided novel insights into the biology of this WNT ligand and the mechanism(s) by which it regulates cortical but not trabecular bone Homeostasis. Most interestingly, Wnt16 appears to be a strong anti-resorptive soluble factor acting on both osteoblasts and osteoclast precursors.

  • vitamin a metabolism action and role in Skeletal Homeostasis
    Endocrine Reviews, 2013
    Co-Authors: Herschel H Conaway, Petra Henning, Ulf H Lerner
    Abstract:

    Vitamin A (retinol) is ingested as either retinyl esters or carotenoids and metabolized to active compounds such as 11-cis-retinal, which is important for vision, and all-trans-retinoic acid, which is the primary mediator of biological actions of vitamin A. All-trans-retinoic acid binds to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors. RAR-retinoid X receptor heterodimers function as transcription factors, binding RAR-responsive elements in promoters of different genes. Numerous cellular functions, including bone cell functions, are mediated by vitamin A; however, it has long been recognized that increased levels of vitamin A can have deleterious effects on bone, resulting in increased Skeletal fragility. Bone mass is dependent on the balance between bone resorption and bone formation. A decrease in bone mass may be caused by either an excess of resorption or decreased bone formation. Early studies indicated that the primary Skeletal effect of vitamin A was to increase bone resorption, but later studies have shown that vitamin A can not only stimulate the formation of bone-resorbing osteoclasts but also inhibit their formation. Effects of vitamin A on bone formation have not been studied in as great a detail and are not as well characterized as effects on bone resorption. Several epidemiological studies have shown an association between vitamin A, decreased bone mass, and osteoporotic fractures, but the data are not conclusive because other studies have found no associations, and some studies have suggested that vitamin A primarily promotes Skeletal health. In this presentation, we have summarized how vitamin A is absorbed and metabolized and how it functions intracellularly. Vitamin A deficiency and excess are introduced, and detailed descriptions of clinical and preclinical studies of the effects of vitamin A on the skeleton are presented.

Charles A Obrien - One of the best experts on this subject based on the ideXlab platform.

  • estrogens and androgens in Skeletal physiology and pathophysiology
    Physical Review, 2017
    Co-Authors: Maria Almeida, Charles A Obrien, Dirk Vanderschueren, Roger Bouillon, Michael R Laurent, Vanessa Dubois, Frank Claessens, Stavros C Manolagas
    Abstract:

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on Skeletal Homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on Skeletal involution.

  • foxo mediated defense against oxidative stress in osteoblasts is indispensable for Skeletal Homeostasis in mice
    Cell Metabolism, 2010
    Co-Authors: Elena Ambrogini, Maria Almeida, Marta Martinmillan, Jihye Paik, Ronald A Depinho, Li Han, Joseph J Goellner, Robert S Weinstein, Robert L Jilka, Charles A Obrien
    Abstract:

    Aging increases oxidative stress and osteoblast apoptosis and decreases bone mass, whereas forkhead box O (FoxO) transcription factors defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Conditional deletion of FoxO1, FoxO3, and FoxO4 in 3-month-old mice resulted in an increase in oxidative stress in bone and osteoblast apoptosis and a decrease in the number of osteoblasts, the rate of bone formation, and bone mass at cancellous and cortical sites. The effect of the deletion on osteoblast apoptosis was cell autonomous and resulted from oxidative stress. Conversely, overexpression of a FoxO3 transgene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis and increased osteoblast number, bone formation rate, and vertebral bone mass. We conclude that FoxO-dependent oxidative defense provides a mechanism to handle the oxygen free radicals constantly generated by the aerobic metabolism of osteoblasts and is thereby indispensable for bone mass Homeostasis.

  • control of bone mass and remodeling by pth receptor signaling in osteocytes
    PLOS ONE, 2008
    Co-Authors: Charles A Obrien, Lilian I Plotkin, Joseph J Goellner, Carlo Galli, Arancha R Gortazar, Matthew R Allen, Alexander G Robling, Mary L Bouxsein, Ernestina Schipani, Charles H Turner
    Abstract:

    Osteocytes, former osteoblasts buried within bone, are thought to orchestrate Skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control Skeletal Homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and -independent mechanisms, respectively.

  • Skeletal involution by age associated oxidative stress and its acceleration by loss of sex steroids
    Journal of Biological Chemistry, 2007
    Co-Authors: Maria Almeida, Lilian I Plotkin, Marta Martinmillan, Li Han, Charles A Obrien, Scott A Stewart, Paula K Roberson, Stavroula Kousteni, Teresita Bellido, Michael A Parfitt
    Abstract:

    Both aging and loss of sex steroids have adverse effects on Skeletal Homeostasis, but whether and how they may influence each others negative impact on bone remains unknown. We report herein that both female and male C57BL/6 mice progressively lost strength (as determined by load-to-failure measurements) and bone mineral density in the spine and femur between the ages of 4 and 31 months. These changes were temporally associated with decreased rate of remodeling as evidenced by decreased osteoblast and osteoclast numbers and decreased bone formation rate; as well as increased osteoblast and osteocyte apoptosis, increased reactive oxygen species levels, and decreased glutathione reductase activity and a corresponding increase in the phosphorylation of p53 and p66shc, two key components of a signaling cascade that are activated by reactive oxygen species and influences apoptosis and lifespan. Exactly the same changes in oxidative stress were acutely reproduced by gonadectomy in 5-month-old females or males and reversed by estrogens or androgens in vivo as well as in vitro.We conclude that the oxidative stress that underlies physiologic organismal aging in mice may be a pivotal pathogenetic mechanism of the age-related bone loss and strength. Loss of estrogens or androgens accelerates the effects of aging on bone by decreasing defense against oxidative stress.

Scott E Youlten - One of the best experts on this subject based on the ideXlab platform.

  • osteocyte transcriptome mapping identifies a molecular landscape controlling Skeletal Homeostasis and susceptibility to Skeletal disease
    Nature Communications, 2021
    Co-Authors: Scott E Youlten, John P Kemp, John G Logan, Elena J Ghirardello, Claudio M Sergio, Michael R G Dack, Siobhan E Guilfoyle, Victoria D Leitch
    Abstract:

    Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different Skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 Skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic Skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human Skeletal disease.

  • osteocyte transcriptome mapping identifies a molecular landscape controlling Skeletal Homeostasis and susceptibility to Skeletal disease
    bioRxiv, 2020
    Co-Authors: Scott E Youlten, John P Kemp, John G Logan, Elena J Ghirardello, Claudio M Sergio, Michael R G Dack, Siobhan E Guilfoyle, Victoria D Leitch
    Abstract:

    Osteocytes are master regulators of the skeleton. We map the transcriptome of osteocytes at different Skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cell-network. We define an osteocyte transcriptome signature, 1239 genes that distinguishes osteocytes from other cells. 77% have no known role in the skeleton. We show they are enriched for genes controlling neuronal network formation, suggesting this program is important in the osteocyte network. We evaluated 19 Skeletal parameters in 733 mouse lines with functional-gene-deletions and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human homologues that cause monogenic Skeletal dysplasias (P=6x10-17), and associated with polygenic diseases, osteoporosis (P=1.8x10-13), and osteoarthritis (P=2.6x10-6). This reveals the molecular landscape that regulates osteocyte network formation and function, and establishes the importance of osteocytes in human Skeletal disease.

Victoria D Leitch - One of the best experts on this subject based on the ideXlab platform.

  • osteocyte transcriptome mapping identifies a molecular landscape controlling Skeletal Homeostasis and susceptibility to Skeletal disease
    Nature Communications, 2021
    Co-Authors: Scott E Youlten, John P Kemp, John G Logan, Elena J Ghirardello, Claudio M Sergio, Michael R G Dack, Siobhan E Guilfoyle, Victoria D Leitch
    Abstract:

    Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different Skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 Skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic Skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human Skeletal disease.

  • osteocyte transcriptome mapping identifies a molecular landscape controlling Skeletal Homeostasis and susceptibility to Skeletal disease
    bioRxiv, 2020
    Co-Authors: Scott E Youlten, John P Kemp, John G Logan, Elena J Ghirardello, Claudio M Sergio, Michael R G Dack, Siobhan E Guilfoyle, Victoria D Leitch
    Abstract:

    Osteocytes are master regulators of the skeleton. We map the transcriptome of osteocytes at different Skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cell-network. We define an osteocyte transcriptome signature, 1239 genes that distinguishes osteocytes from other cells. 77% have no known role in the skeleton. We show they are enriched for genes controlling neuronal network formation, suggesting this program is important in the osteocyte network. We evaluated 19 Skeletal parameters in 733 mouse lines with functional-gene-deletions and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human homologues that cause monogenic Skeletal dysplasias (P=6x10-17), and associated with polygenic diseases, osteoporosis (P=1.8x10-13), and osteoarthritis (P=2.6x10-6). This reveals the molecular landscape that regulates osteocyte network formation and function, and establishes the importance of osteocytes in human Skeletal disease.