GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone.

Abstract:

:Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality of Gdf11 null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show that Gdf11 null mice, despite significantly down-regulating Mstn expression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed in Mstn null mice that display enhanced bone mass. Mechanistically, Mstn deletion up-regulates Gdf11 expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlike Mstn null mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

authors

Suh J,Kim NK,Lee SH,Eom JH,Lee Y,Park JC,Woo KM,Baek JH,Kim JE,Ryoo HM,Lee SJ,Lee YS

doi

10.1073/pnas.1916034117

subject

Has Abstract

pub_date

2020-03-03 00:00:00

pages

4910-4920

issue

9

eissn

0027-8424

issn

1091-6490

pii

1916034117

journal_volume

117

pub_type

杂志文章
  • The maintenance of transferrin polymorphism in pigeons (saccharomyces cerevisiae-eggwhite).

    abstract::Transferrin, a nonheme iron-binding protein, is polymorphic in most vertebrate species that have been examined. In pigeons, it is controlled by an autosomal gene, with two known codominant alleles, Tf(A) and Tf(B). The two alleles are found in nearly equal frequencies and the three genotypes are at Hardy-Weinberg equi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.69.2.326

    authors: Frelinger JA

    更新日期:1972-02-01 00:00:00

  • Tobacco nicotine uptake permease (NUP1) affects alkaloid metabolism.

    abstract::An effective plant alkaloid chemical defense requires a variety of transport processes, but few alkaloid transporters have been characterized at the molecular level. Previously, a gene fragment encoding a putative plasma membrane proton symporter was isolated, because it was coordinately regulated with several nicotin...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1108620108

    authors: Hildreth SB,Gehman EA,Yang H,Lu RH,Ritesh KC,Harich KC,Yu S,Lin J,Sandoe JL,Okumoto S,Murphy AS,Jelesko JG

    更新日期:2011-11-01 00:00:00

  • beta 2 nicotinic acetylcholine receptor subunit modulates protective responses to stress: A receptor basis for sleep-disordered breathing after nicotine exposure.

    abstract::Nicotine exposure diminishes the protective breathing and arousal responses to stress (hypoxia). By exacerbating sleep-disordered breathing, this disturbance could underpin the well established association between smoking and the increased risk of sudden infant death syndrome. We show here that the protective response...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.192463599

    authors: Cohen G,Han ZY,Grailhe R,Gallego J,Gaultier C,Changeux JP,Lagercrantz H

    更新日期:2002-10-01 00:00:00

  • Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity.

    abstract::ATP-dependent DNA supercoiling catalyzed by Escherichia coli DNA gyrase was inhibited by oxolinic acid, a compound similar to but more potent than nalidixic acid and a known inhibitor of DNA replication in E. coli. The supercoiling activity of DNA gyrase purified from nalidixic acid-resistant mutant (nalA(R)) bacteria...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.74.11.4772

    authors: Gellert M,Mizuuchi K,O'Dea MH,Itoh T,Tomizawa JI

    更新日期:1977-11-01 00:00:00

  • Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe.

    abstract::Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their charac...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 历史文章,杂志文章

    doi:10.1073/pnas.1901169116

    authors: Frantz LAF,Haile J,Lin AT,Scheu A,Geörg C,Benecke N,Alexander M,Linderholm A,Mullin VE,Daly KG,Battista VM,Price M,Gron KJ,Alexandri P,Arbogast RM,Arbuckle B,Bӑlӑşescu A,Barnett R,Bartosiewicz L,Baryshnikov G,Bons

    更新日期:2019-08-27 00:00:00

  • Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma.

    abstract::Translocations involving c-myc and an Ig locus have been reported rarely in human multiple myeloma (MM). Using specific fluorescence in situ hybridization probes, we show complex karyotypic abnormalities of the c-myc or L-myc locus in 19 of 20 MM cell lines and approximately 50% of advanced primary MM tumors. These ab...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.97.1.228

    authors: Shou Y,Martelli ML,Gabrea A,Qi Y,Brents LA,Roschke A,Dewald G,Kirsch IR,Bergsagel PL,Kuehl WM

    更新日期:2000-01-04 00:00:00

  • Cu isotopes in marine black shales record the Great Oxidation Event.

    abstract::The oxygenation of the atmosphere ∼2.45-2.32 billion years ago (Ga) is one of the most significant geological events to have affected Earth's redox history. Our understanding of the timing and processes surrounding this key transition is largely dependent on the development of redox-sensitive proxies, many of which re...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1523544113

    authors: Chi Fru E,Rodríguez NP,Partin CA,Lalonde SV,Andersson P,Weiss DJ,El Albani A,Rodushkin I,Konhauser KO

    更新日期:2016-05-03 00:00:00

  • African climate response to orbital and glacial forcing in 140,000-y simulation with implications for early modern human environments.

    abstract::A climate/vegetation model simulates episodic wetter and drier periods at the 21,000-y precession period in eastern North Africa, the Arabian Peninsula, and the Levant over the past 140,000 y. Large orbitally forced wet/dry extremes occur during interglacial time, ∼130 to 80 ka, and conditions between these two extrem...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1917673117

    authors: Kutzbach JE,Guan J,He F,Cohen AS,Orland IJ,Chen G

    更新日期:2020-02-04 00:00:00

  • IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells.

    abstract::Expression of T1ST2, the IL-33R, by Th2 cells requires GATA3. Resting Th2 cells express little GATA3, which is increased by IL-33 and a STAT5 activator, in turn increasing T1ST2 from its low-level expression on resting Th2 cells. Th2 cells that have upregulated T1ST2 produce IL-13, but not IL-4, in response to IL-33 p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0906988106

    authors: Guo L,Wei G,Zhu J,Liao W,Leonard WJ,Zhao K,Paul W

    更新日期:2009-08-11 00:00:00

  • Atomically detailed simulation of the recovery stroke in myosin by Milestoning.

    abstract::Myosin II is a molecular motor that converts chemical to mechanical energy and enables muscle operations. After a power stroke, a recovery transition completes the cycle and returns the molecular motor to its prestroke state. Atomically detailed simulations in the framework of the Milestoning theory are used to calcul...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0909636107

    authors: Elber R,West A

    更新日期:2010-03-16 00:00:00

  • Postsynaptic alpha-adrenergic receptors potentiate the beta-adrenergic stimulation of pineal serotonin N-acetyltransferase.

    abstract::The role played by postsynaptic alpha-adrenergic receptors in the stimulation of pineal N-acetyltransferase (EC 2.3.1.5) and [3H]melatonin production was investigated in the rat. In vivo studies indicated that phenylephrine, an alpha-adrenergic agonist, potentiated and prolonged the effects of isoproterenol, a beta-ad...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.2.599

    authors: Klein DC,Sugden D,Weller JL

    更新日期:1983-01-01 00:00:00

  • 14-3-3 proteins associate with cdc25 phosphatases.

    abstract::The cdc25 phosphatases play key roles in cell cycle progression by activating cyclin-dependent kinases. Two members of the 14-3-3 protein family have been isolated in a yeast two-hybrid screen designed to identify proteins that interact with the human cdc25A and cdc25B phosphatases. Genes encoding the human homolog of...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.17.7892

    authors: Conklin DS,Galaktionov K,Beach D

    更新日期:1995-08-15 00:00:00

  • ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis.

    abstract::Heparin is the most widely prescribed biopharmaceutical in production globally. Its potent anticoagulant activity and safety makes it the drug of choice for preventing deep vein thrombosis and pulmonary embolism. In 2008, adulterated material was introduced into the heparin supply chain, resulting in several hundred d...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1920880117

    authors: Weiss RJ,Spahn PN,Toledo AG,Chiang AWT,Kellman BP,Li J,Benner C,Glass CK,Gordts PLSM,Lewis NE,Esko JD

    更新日期:2020-04-28 00:00:00

  • The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation.

    abstract::Protein-protein and protein-ligand interactions are ubiquitous in a biological cell. Here, we report a comprehensive study of the distribution of protein-ligand interaction sites, namely ligand-binding pockets, around protein-protein interfaces where protein-protein interactions occur. We inspected a representative se...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1117768109

    authors: Gao M,Skolnick J

    更新日期:2012-03-06 00:00:00

  • Homolog of tocopherol C methyltransferases catalyzes N methylation in anticancer alkaloid biosynthesis.

    abstract::Madagascar periwinkle (Catharanthus roseus) is the sole source of the anticancer drugs vinblastine and vincristine, bisindole alkaloids derived from the dimerization of the terpenoid indole alkaloids vindoline and catharanthine. Full elucidation of the biosynthetic pathways of these compounds is a prerequisite for met...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1009003107

    authors: Liscombe DK,Usera AR,O'Connor SE

    更新日期:2010-11-02 00:00:00

  • In vitro suicide inhibition of self-splicing of a group I intron from Pneumocystis carinii by an N3' --> P5' phosphoramidate hexanucleotide.

    abstract::Binding enhancement by tertiary interactions is a strategy that takes advantage of the higher order folding of functionally important RNAs to bind short nucleic acid-based compounds tightly and more specifically than possible by simple base pairing. For example, tertiary interactions enhance binding of specific hexame...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.6.2734

    authors: Testa SM,Gryaznov SM,Turner DH

    更新日期:1999-03-16 00:00:00

  • Nucleotide sequence and predicted amino acid sequence of a protein encoded in a small herpes simplex virus DNA fragment capable of trans-inducing alpha genes.

    abstract::The five alpha genes of herpes simplex virus 1 are the first set of genes to be expressed after infection. Previous studies have shown that alpha genes resident in eukaryotic cells are induced by infection with herpes simplex virus 1 or 2 but not by other herpesviruses and indicate that the alpha trans-inducing factor...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.17.5870

    authors: Pellett PE,McKnight JL,Jenkins FJ,Roizman B

    更新日期:1985-09-01 00:00:00

  • Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.

    abstract::A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance--wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on f...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1423952112

    authors: Vatner DF,Majumdar SK,Kumashiro N,Petersen MC,Rahimi Y,Gattu AK,Bears M,Camporez JP,Cline GW,Jurczak MJ,Samuel VT,Shulman GI

    更新日期:2015-01-27 00:00:00

  • High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells.

    abstract::Most human cancers are aneuploid and have chromosomal instability, which contrasts to the inability of human cells to normally tolerate aneuploidy. Noting that aneuploidy in human breast cancer correlates with increased expression levels of the Mps1 checkpoint gene, we investigated whether these high levels of Mps1 co...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1007645108

    authors: Daniel J,Coulter J,Woo JH,Wilsbach K,Gabrielson E

    更新日期:2011-03-29 00:00:00

  • A strategy to capture and characterize the synaptic transcriptome.

    abstract::Here we describe a strategy designed to identify RNAs that are actively transported to synapses during learning. Our approach is based on the characterization of RNA transport complexes carried by molecular motor kinesin. Using this strategy in Aplysia, we have identified 5,657 unique sequences consisting of both codi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1304422110

    authors: Puthanveettil SV,Antonov I,Kalachikov S,Rajasethupathy P,Choi YB,Kohn AB,Citarella M,Yu F,Karl KA,Kinet M,Morozova I,Russo JJ,Ju J,Moroz LL,Kandel ER

    更新日期:2013-04-30 00:00:00

  • Cell division cycle 6, a mitotic substrate of polo-like kinase 1, regulates chromosomal segregation mediated by cyclin-dependent kinase 1 and separase.

    abstract::Defining the links between cell division and DNA replication is essential for understanding normal cell cycle progression and tumorigenesis. In this report we explore the effect of phosphorylation of cell division cycle 6 (Cdc6), a DNA replication initiation factor, by polo-like kinase 1 (Plk1) on the regulation of ch...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1013557107

    authors: Yim H,Erikson RL

    更新日期:2010-11-16 00:00:00

  • B cells are critical for autoimmune pathology in Scurfy mice.

    abstract::Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1313547110

    authors: Aschermann S,Lehmann CH,Mihai S,Schett G,Dudziak D,Nimmerjahn F

    更新日期:2013-11-19 00:00:00

  • An adenovirus type 5 early gene function regulates expression of other early viral genes.

    abstract::We have identified an adenovirus type 5(Ad5) early gene function located in early region 1 which is required for the production of early cytoplasmic mRNAs corresponding to early regions 2, 3, and 4. Mutant dl312 (lacks the segment between 1.5 and 4.5 map units) grows as well as wild-type virus in 293 cells (Ad5-trans...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.8.3665

    authors: Jones N,Shenk T

    更新日期:1979-08-01 00:00:00

  • Novel free radicals in synthetic and natural pheomelanins: distinction between dopa melanins and cysteinyldopa melanins by ESR spectroscopy.

    abstract::Synthetic pheomelanins from enzymic oxidation of the 3,4-dihydroxyphenylalanine (dopa) derivative 5-S-cysteinyldopa have been examined by ESR spectroscopy. These alkalisoluble polymers contain a novel kind of free radical that is spectroscopically distinct from that found in eumelanins. Delocalization of the unpaired ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.9.2885

    authors: Sealy RC,Hyde JS,Felix CC,Menon IA,Prota G,Swartz HM,Persad S,Haberman HF

    更新日期:1982-05-01 00:00:00

  • Deamidation of human proteins.

    abstract::Deamidation of asparaginyl and glutaminyl residues causes time-dependent changes in charge and conformation of peptides and proteins. Quantitative and experimentally verified predictive calculations of the deamidation rates of 1,371 asparaginyl residues in a representative collection of 126 human proteins have been pe...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.221463198

    authors: Robinson NE,Robinson AB

    更新日期:2001-10-23 00:00:00

  • Cloning and sequence analysis of cDNA for the precursor of human growth hormone-releasing factor, somatocrinin.

    abstract::Molecular cloning has established the primary structures of two precursors of the human pancreas growth hormone-releasing factor (hpGRF-44), somatocrinin. Both polypeptides contain the sequence of hpGRF-44 flanked by basic processing sites. Furthermore, the precursors include a putative signal sequence and a carboxyl-...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.14.4311

    authors: Gubler U,Monahan JJ,Lomedico PT,Bhatt RS,Collier KJ,Hoffman BJ,Böhlen P,Esch F,Ling N,Zeytin F,Brazeau P,Poonian MS,Gage LP

    更新日期:1983-07-01 00:00:00

  • STRUBBELIG defines a receptor kinase-mediated signaling pathway regulating organ development in Arabidopsis.

    abstract::An open question remains as to what coordinates cell behavior during organogenesis, permitting organs to reach their appropriate size and shape. The Arabidopsis gene STRUBBELIG (SUB) defines a receptor-mediated signaling pathway in plants. SUB encodes a putative leucine-rich repeat transmembrane receptor-like kinase. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0503526102

    authors: Chevalier D,Batoux M,Fulton L,Pfister K,Yadav RK,Schellenberg M,Schneitz K

    更新日期:2005-06-21 00:00:00

  • Multiplexed variation scanning for 1,000 amplicons in hundreds of patients using mismatch repair detection (MRD) on tag arrays.

    abstract::Identification of the genetic basis of common disease may require comprehensive sequence analysis of coding regions and regulatory elements in patients and controls to find genetic effects caused by rare or heterogeneous mutations. In this study, we demonstrate how mismatch repair detection on tag arrays can be applie...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0506677102

    authors: Faham M,Zheng J,Moorhead M,Fakhrai-Rad H,Namsaraev E,Wong K,Wang Z,Chow SG,Lee L,Suyenaga K,Reichert J,Boudreau A,Eberle J,Bruckner C,Jain M,Karlin-Neumann G,Jones HB,Willis TD,Buxbaum JD,Davis RW

    更新日期:2005-10-11 00:00:00

  • Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading.

    abstract::Cell migration and spreading involve the coordination of membrane trafficking, actomyosin contraction, and modifications to plasma membrane tension and area. The biochemical or biophysical basis for this coordination is however unknown. In this study, we show that during cell spreading, lamellipodia protrusion flatten...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1105845108

    authors: Gauthier NC,Fardin MA,Roca-Cusachs P,Sheetz MP

    更新日期:2011-08-30 00:00:00

  • Insulin-like growth factor II signaling through the insulin-like growth factor II/mannose-6-phosphate receptor promotes exocytosis in insulin-secreting cells.

    abstract::The insulin-like growth factor II (IGF-II)/mannose-6-phosphate (M-6-P) receptor is known to participate in endocytosis as well as sorting of lysosomal enzymes and is involved in membrane trafficking through rapid cycling between cytosolic membrane compartments and the plasma membrane. Here we demonstrate that IGF-II, ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.12.6232

    authors: Zhang Q,Tally M,Larsson O,Kennedy RT,Huang L,Hall K,Berggren PO

    更新日期:1997-06-10 00:00:00