Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development

Ratzka A, Kalus I, Moser M, Dierks T, Mundlos S, Vortkamp A (2008)

Zeitschriftenaufsatz | Veröffentlicht | Englisch
Es wurden keine Dateien hochgeladen. Nur Publikationsnachweis!
Ratzka, Andreas; Kalus, InaUniBi; Moser, Markus; Dierks, ThomasUniBi; Mundlos, Stefan; Vortkamp, Andrea
Abstract / Bemerkung
Modification of the sulfation pattern of heparan sulfate (HS) during organ development is thought to regulate binding and signal transduction of several growth factors. The secreted sulfatases, Sulf1 and Sulf2, desulfate HS on 6-O-positions extracellularly. We show that both sulfatases are expressed in overlapping patterns during embryonic skeletal development. Analysis of compound mutants of Sulf1 and Sulf2 derived from gene trap insertions and targeted null alleles revealed subtle but distinct skeletal malformations including reduced bone length, premature vertebrae ossification and fusions of sternebrae and tail vertebrae. Molecular analysis of endochondral ossification points to a function of Sulf1 and Sulf2 in delaying the differentiation of endochondral bones. Penetrance and severity of the phenotype increased with reduced numbers of functional alleles indicating redundant functions of both sulfatases. The mild skeletal phenotype of double mutants suggests a role for extracellular modification of 6-O-sulfation in fine-tuning rather than regulating the development of skeletal structures.
heparan sulfate; ossification; endochondral; chondrocyte differentiation; bone; sulfatase; cartilage; Sulf2; Sulf1; mouse
Page URI


Ratzka A, Kalus I, Moser M, Dierks T, Mundlos S, Vortkamp A. Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. DEVELOPMENTAL DYNAMICS. 2008;237(2):339-353.
Ratzka, A., Kalus, I., Moser, M., Dierks, T., Mundlos, S., & Vortkamp, A. (2008). Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. DEVELOPMENTAL DYNAMICS, 237(2), 339-353.
Ratzka, Andreas, Kalus, Ina, Moser, Markus, Dierks, Thomas, Mundlos, Stefan, and Vortkamp, Andrea. 2008. “Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development”. DEVELOPMENTAL DYNAMICS 237 (2): 339-353.
Ratzka, A., Kalus, I., Moser, M., Dierks, T., Mundlos, S., and Vortkamp, A. (2008). Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. DEVELOPMENTAL DYNAMICS 237, 339-353.
Ratzka, A., et al., 2008. Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. DEVELOPMENTAL DYNAMICS, 237(2), p 339-353.
A. Ratzka, et al., “Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development”, DEVELOPMENTAL DYNAMICS, vol. 237, 2008, pp. 339-353.
Ratzka, A., Kalus, I., Moser, M., Dierks, T., Mundlos, S., Vortkamp, A.: Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. DEVELOPMENTAL DYNAMICS. 237, 339-353 (2008).
Ratzka, Andreas, Kalus, Ina, Moser, Markus, Dierks, Thomas, Mundlos, Stefan, and Vortkamp, Andrea. “Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development”. DEVELOPMENTAL DYNAMICS 237.2 (2008): 339-353.

46 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
Zheng C, Lin X, Xu X, Wang C, Zhou J, Gao B, Fan J, Lu W, Hu Y, Jie Q, Luo Z, Yang L., EBioMedicine 40(), 2019
PMID: 30685387
Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma.
Chen G, Nakamura I, Dhanasekaran R, Iguchi E, Tolosa EJ, Romecin PA, Vera RE, Almada LL, Miamen AG, Chaiteerakij R, Zhou M, Asiedu MK, Moser CD, Han S, Hu C, Banini BA, Oseini AM, Chen Y, Fang Y, Yang D, Shaleh HM, Wang S, Wu D, Song T, Lee JS, Thorgeirsson SS, Chevet E, Shah VH, Fernandez-Zapico ME, Roberts LR., Cancer Res 77(3), 2017
PMID: 27872089
Genomic prediction of reproduction traits for Merino sheep.
Bolormaa S, Brown DJ, Swan AA, van der Werf JHJ, Hayes BJ, Daetwyler HD., Anim Genet 48(3), 2017
PMID: 28211150
Desulfation of Heparan Sulfate by Sulf1 and Sulf2 Is Required for Corticospinal Tract Formation.
Okada T, Keino-Masu K, Nagamine S, Kametani F, Ohto T, Hasegawa M, van Kuppevelt TH, Kunita S, Takahashi S, Masu M., Sci Rep 7(1), 2017
PMID: 29062064
Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing.
Zaman G, Staines KA, Farquharson C, Newton PT, Dudhia J, Chenu C, Pitsillides AA, Dhoot GK., Histochem Cell Biol 145(1), 2016
PMID: 26464246
The role of heparan sulphate in development: the ectodermal story.
Coulson-Thomas VJ., Int J Exp Pathol 97(3), 2016
PMID: 27385054
Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length.
Mis EK, Liem KF, Kong Y, Schwartz NB, Domowicz M, Weatherbee SD., Dev Biol 385(1), 2014
PMID: 24161523
The association of arylendosulfatase 1 (SULF1) gene polymorphism with recurrent miscarriage.
Zahraei M, Sheikhha MH, Kalantar SM, Ghasemi N, Jahaninejad T, Rajabi S, Mohammadpour H., J Assist Reprod Genet 31(2), 2014
PMID: 24322345
Heparan sulfate as a regulator of endochondral ossification and osteochondroma development.
Jochmann K, Bachvarova V, Vortkamp A., Matrix Biol 34(), 2014
PMID: 24370655
The heparan sulfate editing enzyme Sulf1 plays a novel role in zebrafish VegfA mediated arterial venous identity.
Gorsi B, Liu F, Ma X, Chico TJ, v A, Kramer KL, Bridges E, Monteiro R, Harris AL, Patient R, Stringer SE., Angiogenesis 17(1), 2014
PMID: 23959107
A genome-wide methylation study on essential hypertension in young African American males.
Wang X, Falkner B, Zhu H, Shi H, Su S, Xu X, Sharma AK, Dong Y, Treiber F, Gutin B, Harshfield G, Snieder H., PLoS One 8(1), 2013
PMID: 23325143
Role of heparan sulfatases in ovarian and breast cancer.
Khurana A, Beleford D, He X, Chien J, Shridhar V., Am J Cancer Res 3(1), 2013
PMID: 23359864
Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues.
Ehlen HW, Chinenkova M, Moser M, Munter HM, Krause Y, Gross S, Brachvogel B, Wuelling M, Kornak U, Vortkamp A., J Bone Miner Res 28(2), 2013
PMID: 22936354
Proteoglycans and their roles in brain cancer.
Wade A, Robinson AE, Engler JR, Petritsch C, James CD, Phillips JJ., FEBS J 280(10), 2013
PMID: 23281850
Endosulfatases SULF1 and SULF2 limit Chlamydia muridarum infection.
Kim JH, Chan C, Elwell C, Singer MS, Dierks T, Lemjabbar-Alaoui H, Rosen SD, Engel JN., Cell Microbiol 15(9), 2013
PMID: 23480519
Cooperation of binding sites at the hydrophilic domain of cell-surface sulfatase Sulf1 allows for dynamic interaction of the enzyme with its substrate heparan sulfate.
Milz F, Harder A, Neuhaus P, Breitkreuz-Korff O, Walhorn V, Lübke T, Anselmetti D, Dierks T., Biochim Biophys Acta 1830(11), 2013
PMID: 23891937
Organ-specific sulfation patterns of heparan sulfate generated by extracellular sulfatases Sulf1 and Sulf2 in mice.
Nagamine S, Tamba M, Ishimine H, Araki K, Shiomi K, Okada T, Ohto T, Kunita S, Takahashi S, Wismans RG, van Kuppevelt TH, Masu M, Keino-Masu K., J Biol Chem 287(12), 2012
PMID: 22298771
Roles of heparan sulfate sulfation in dentinogenesis.
Hayano S, Kurosaka H, Yanagita T, Kalus I, Milz F, Ishihara Y, Islam MN, Kawanabe N, Saito M, Kamioka H, Adachi T, Dierks T, Yamashiro T., J Biol Chem 287(15), 2012
PMID: 22351753
Genomic variation in seven Khoe-San groups reveals adaptation and complex African history.
Schlebusch CM, Skoglund P, Sjödin P, Gattepaille LM, Hernandez D, Jay F, Li S, De Jongh M, Singleton A, Blum MG, Soodyall H, Jakobsson M., Science 338(6105), 2012
PMID: 22997136
HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells.
Khurana A, Liu P, Mellone P, Lorenzon L, Vincenzi B, Datta K, Yang B, Linhardt RJ, Lingle W, Chien J, Baldi A, Shridhar V., Cancer Res 71(6), 2011
PMID: 21266348
Ihh signaling regulates mandibular symphysis development and growth.
Sugito H, Shibukawa Y, Kinumatsu T, Yasuda T, Nagayama M, Yamada S, Minugh-Purvis N, Pacifici M, Koyama E., J Dent Res 90(5), 2011
PMID: 21297010
WT1-dependent sulfatase expression maintains the normal glomerular filtration barrier.
Schumacher VA, Schlötzer-Schrehardt U, Karumanchi SA, Shi X, Zaia J, Jeruschke S, Zhang D, Pavenstädt H, Drenckhan A, Amann K, Ng C, Hartwig S, Ng KH, Ho J, Kreidberg JA, Taglienti M, Royer-Pokora B, Ai X., J Am Soc Nephrol 22(7), 2011
PMID: 21719793
Heparan sulfate proteoglycans.
Sarrazin S, Lamanna WC, Esko JD., Cold Spring Harb Perspect Biol 3(7), 2011
PMID: 21690215
Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.
Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang YQ, Tsay D, He B, Jablons DM, Rosen SD., Oncogene 29(5), 2010
PMID: 19855436
HpSulf, a heparan sulfate 6-O-endosulfatase, is involved in the regulation of VEGF signaling during sea urchin development.
Fujita K, Takechi E, Sakamoto N, Sumiyoshi N, Izumi S, Miyamoto T, Matsuura S, Tsurugaya T, Akasaka K, Yamamoto T., Mech Dev 127(3-4), 2010
PMID: 20036737
Regulation of intracellular signaling by extracellular glycan remodeling.
Parker RB, Kohler JJ., ACS Chem Biol 5(1), 2010
PMID: 19968325
Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways.
Otsuki S, Hanson SR, Miyaki S, Grogan SP, Kinoshita M, Asahara H, Wong CH, Lotz MK., Proc Natl Acad Sci U S A 107(22), 2010
PMID: 20479257
Expression patterns of sulfatase genes in the developing mouse embryo.
Ratzka A, Mundlos S, Vortkamp A., Dev Dyn 239(6), 2010
PMID: 20503373
Mesomelia-synostoses syndrome results from deletion of SULF1 and SLCO5A1 genes at 8q13.
Isidor B, Pichon O, Redon R, Day-Salvatore D, Hamel A, Siwicka KA, Bitner-Glindzicz M, Heymann D, Kjellén L, Kraus C, Leroy JG, Mortier GR, Rauch A, Verloes A, David A, Le Caignec C., Am J Hum Genet 87(1), 2010
PMID: 20602915
Sulfatase modifying factor 1-mediated fibroblast growth factor signaling primes hematopoietic multilineage development.
Buono M, Visigalli I, Bergamasco R, Biffi A, Cosma MP., J Exp Med 207(8), 2010
PMID: 20643830
Mice lacking the orphan receptor ror1 have distinct skeletal abnormalities and are growth retarded.
Lyashenko N, Weissenböck M, Sharir A, Erben RG, Minami Y, Hartmann C., Dev Dyn 239(8), 2010
PMID: 20593419
Sulf-2: an extracellular modulator of cell signaling and a cancer target candidate.
Rosen SD, Lemjabbar-Alaoui H., Expert Opin Ther Targets 14(9), 2010
PMID: 20629619
Functional consequences of the subdomain organization of the sulfs.
Tang R, Rosen SD., J Biol Chem 284(32), 2009
PMID: 19520866
Rapid purification and high sensitivity analysis of heparan sulfate from cells and tissues: toward glycomics profiling.
Guimond SE, Puvirajesinghe TM, Skidmore MA, Kalus I, Dierks T, Yates EA, Turnbull JE., J Biol Chem 284(38), 2009
PMID: 19596853
Characterization of the human sulfatase Sulf1 and its high affinity heparin/heparan sulfate interaction domain.
Frese MA, Milz F, Dick M, Lamanna WC, Dierks T., J Biol Chem 284(41), 2009
PMID: 19666466
Modelling neurofibromatosis type 1 tibial dysplasia and its treatment with lovastatin.
Kolanczyk M, Kühnisch J, Kossler N, Osswald M, Stumpp S, Thurisch B, Kornak U, Mundlos S., BMC Med 6(), 2008
PMID: 18671844
Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.
Lai JP, Thompson JR, Sandhu DS, Roberts LR., Future Oncol 4(6), 2008
PMID: 19086847

42 References

Daten bereitgestellt von Europe PubMed Central.

QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling.
Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson CP Jr., J. Cell Biol. 162(2), 2003
PMID: 12860968
SULF1 and SULF2 regulate heparan sulfate-mediated GDNF signaling for esophageal innervation.
Ai X, Kitazawa T, Do AT, Kusche-Gullberg M, Labosky PA, Emerson CP Jr., Development 134(18), 2007
PMID: 17720696
Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library.
Ashikari-Hada S, Habuchi H, Kariya Y, Itoh N, Reddi AH, Kimata K., J. Biol. Chem. 279(13), 2004
PMID: 14707131
A somitic compartment of tendon progenitors.
Brent AE, Schweitzer R, Tabin CJ., Cell 113(2), 2003
PMID: 12705871
An early role for sonic hedgehog from foregut endoderm in jaw development: ensuring neural crest cell survival.
Brito JM, Teillet MA, Le Douarin NM., Proc. Natl. Acad. Sci. U.S.A. 103(31), 2006
PMID: 16868080
Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase.
Bullock SL, Fletcher JM, Beddington RS, Wilson VA., Genes Dev. 12(12), 1998
PMID: 9637690
Studies on the morphogenesis of the mouse sternum. I. Normal embryonic development
Chen, J Anat Lond 86(), 1952
Studies on the morphogenesis of the mouse sternum. III. Experiments on the closure and segmentation of the sternal bands
Chen, J Anat Lond 87(), 1953
Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA., Nature 383(6599), 1996
PMID: 8837770
Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase.
Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson CP Jr., Science 293(5535), 2001
PMID: 11533491
Heparan sulfate proteoglycans: key players in cartilage biology.
Farach-Carson MC, Hecht JT, Carson DD., Crit. Rev. Eukaryot. Gene Expr. 15(1), 2005
PMID: 15831077
The control of chondrogenesis.
Goldring MB, Tsuchimochi K, Ijiri K., J. Cell. Biochem. 97(1), 2006
PMID: 16215986
Tinkering with heparan sulfate sulfation to steer development.
Gorsi B, Stringer SE., Trends Cell Biol. 17(4), 2007
PMID: 17320398
Cerebral hypoplasia and craniofacial defects in mice lacking heparan sulfate Ndst1 gene function.
Grobe K, Inatani M, Pallerla SR, Castagnola J, Yamaguchi Y, Esko JD., Development 132(16), 2005
PMID: 16020517
Secreted sulfatases Sulf1 and Sulf2 have overlapping yet essential roles in mouse neonatal survival
Holst, PLoS one e575(), 2007
Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification.
Koziel L, Kunath M, Kelly OG, Vortkamp A., Dev. Cell 6(6), 2004
PMID: 15177029
Developmental regulation of the growth plate.
Kronenberg HM., Nature 423(6937), 2003
PMID: 12748651
Heparan sulfate 6-O-endosulfatases: discrete in vivo activities and functional co-operativity.
Lamanna WC, Baldwin RJ, Padva M, Kalus I, Ten Dam G, van Kuppevelt TH, Gallagher JT, von Figura K, Dierks T, Merry CL., Biochem. J. 400(1), 2006
PMID: 16901266
The heparanome--the enigma of encoding and decoding heparan sulfate sulfation.
Lamanna WC, Kalus I, Padva M, Baldwin RJ, Merry CL, Dierks T., J. Biotechnol. 129(2), 2007
PMID: 17337080
Heparan sulfate structure in mice with genetically modified heparan sulfate production.
Ledin J, Staatz W, Li JP, Gotte M, Selleck S, Kjellen L, Spillmann D., J. Biol. Chem. 279(41), 2004
PMID: 15292174
Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18.
Liu Z, Xu J, Colvin JS, Ornitz DM., Genes Dev. 16(7), 2002
PMID: 11937493
Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase gene, Sulf2.
Lum DH, Tan J, Rosen SD, Werb Z., Mol. Cell. Biol. 27(2), 2006
PMID: 17116694
The molecular phenotype of heparan sulfate in the Hs2st-/- mutant mouse.
Merry CL, Bullock SL, Swan DC, Backen AC, Lyon M, Beddington RS, Wilson VA, Gallagher JT., J. Biol. Chem. 276(38), 2001
PMID: 11457822
Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation.
Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A., Dev. Cell 3(3), 2002
PMID: 12361605
Expression of Fgf and Tgfbeta signaling related genes during embryonic endochondral ossification.
Minina E, Schneider S, Rosowski M, Lauster R, Vortkamp A., Gene Expr. Patterns 6(1), 2005
PMID: 15963767
Expression of a heparan sulfate remodeling enzyme, heparan sulfate 6-O-endosulfatase sulfatase FP2, in the rat nervous system.
Nagamine S, Koike S, Keino-Masu K, Masu M., Brain Res. Dev. Brain Res. 159(2), 2005
PMID: 16139897
Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells
Nawroth, PLoS one e392(), 2007
Identification of a novel nonlysosomal sulphatase expressed in the floor plate, choroid plexus and cartilage.
Ohto T, Uchida H, Yamazaki H, Keino-Masu K, Matsui A, Masu M., Genes Cells 7(2), 2002
PMID: 11895481
Chondrodysplasias due to proteoglycan defects.
Schwartz NB, Domowicz M., Glycobiology 12(4), 2002
PMID: 12042245
Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome.
Stricker S, Verhey van Wijk N, Witte F, Brieske N, Seidel K, Mundlos S., Dev. Dyn. 235(12), 2006
PMID: 17061261
BayGenomics: a resource of insertional mutations in mouse embryonic stem cells.
Stryke D, Kawamoto M, Huang CC, Johns SJ, King LA, Harper CA, Meng EC, Lee RE, Yee A, L'Italien L, Chuang PT, Young SG, Skarnes WC, Babbitt PC, Ferrin TE., Nucleic Acids Res. 31(1), 2003
PMID: 12520002
Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement.
Thiele H, Sakano M, Kitagawa H, Sugahara K, Rajab A, Hohne W, Ritter H, Leschik G, Nurnberg P, Mundlos S., Proc. Natl. Acad. Sci. U.S.A. 101(27), 2004
PMID: 15215498
Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.
Viviano BL, Paine-Saunders S, Gasiunas N, Gallagher J, Saunders S., J. Biol. Chem. 279(7), 2003
PMID: 14645250
QSulf1, a heparan sulfate 6-O-endosulfatase, inhibits fibroblast growth factor signaling in mesoderm induction and angiogenesis.
Wang S, Ai X, Freeman SD, Pownall ME, Lu Q, Kessler DS, Emerson CP Jr., Proc. Natl. Acad. Sci. U.S.A. 101(14), 2004
PMID: 15051888
The genetic basis for skeletal diseases.
Zelzer E, Olsen BR., Nature 423(6937), 2003
PMID: 12748653
Sulf1 expression pattern and its role in cartilage and joint development.
Zhao W, Sala-Newby GB, Dhoot GK., Dev. Dyn. 235(12), 2006
PMID: 17061267

Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®

PMID: 18213582
PubMed | Europe PMC

Suchen in

Google Scholar