Expression profile of <i>Papss2</i> (3′‐phosphoadenosine 5′‐phosphosulfate synthase 2) during cartilage formation and skeletal development in the mouse embryo

Stelzer, Christiane; Brimmer, Annette; Hermanns, Pia; Zabel, Bernhard; Dietz, Uwe

doi:10.1002/dvdy.21137

Cited by 55 publications

(47 citation statements)

References 22 publications

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“…3H). Papss1, by contrast, was detected at very low levels in both wild-type and bm cartilage by in situ (data not shown), as previously demonstrated on mouse cartilage at late developmental stages (Stelzer et al, 2007). However, northern blot analysis (see Fig.…”

Section: Analysis Of the Brachymorphic Mouse Growth Platesupporting

confidence: 83%

Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate

2009

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In contrast to the functional role of heparan sulfate proteoglycans (HSPGs), the importance of chondroitin sulfate proteoglycans (CSPGs) in modulating signaling pathways involving hedgehog proteins, wingless-related proteins and fibroblast growth factors remains unclear. To elucidate the importance of sulfated CSPGs in signaling paradigms required for endochondral bone formation, the brachymorphic (bm) mouse was used as a model for undersulfated CSPGs. The bm mouse exhibits a postnatal chondrodysplasia caused by a mutation in the phosphoadenosine phosphosulfate (PAPS) synthetase (Papss2) gene, leading to reduced levels of PAPS and undersulfated proteoglycans. Biochemical analysis of the glycosaminoglycan (GAG) content in bm cartilage via sulfate labeling and fluorophore-assisted carbohydrate electrophoresis revealed preferential undersulfation of chondroitin chains (CS) and normal sulfation of heparan sulfate chains. In situ hybridization and immunohistochemical analysis of bm limb growth plates showed diminished Indian hedgehog (Ihh) signaling and abnormal Ihh protein distribution in the extracellular matrix. Consistent with the decrease in hedgehog signaling, BrdU incorporation exhibited a significant reduction in chondrocyte proliferation. Direct measurements of Ihh binding to defined GAG chains demonstrated that Ihh interacts with CS, particularly chondroitin-4-sulfate. Furthermore, co-immunoprecipitation experiments showed that Ihh binds to the major cartilage CSPG aggrecan via its CS chains. Overall, this study demonstrates an important function for CSPGs in modulating Ihh signaling in the developing growth plate, and highlights the importance of carbohydrate sulfation in regulating growth factor signaling.

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Section: Analysis Of the Brachymorphic Mouse Growth Platesupporting

confidence: 83%

Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate

2009

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“…PAPSS2, which also belongs to this category, is of particular interest because this gene is found in proliferating chondrocytes in embryogenesis, but is dramatically downregulated in hypertrophic chondrocytes. 20 Among the most similarly expressed genes, we also found UNQ830. The protein has not yet been functionally identified, but shows a very high similarity to COL2 and other matrix proteins and might therefore be involved in ECM organization.…”

Section: Figmentioning

confidence: 86%

Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells in Self-Gelling Alginate Discs Reveals Novel Chondrogenic Signature Gene Clusters

Herlofsen

Küchler

Melvik

et al. 2011

Tissue Engineering Part A

103

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We have used a disc-shaped self-gelling alginate hydrogel as a scaffold for in vitro chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells. The comparison of monolayer cells and alginate embedded cells with or without differentiation medium allowed us to perform a detailed kinetic study of the expression of a range of genes and proteins known to be involved in chondrogenesis, using real-time polymerase chain reaction, fluorescence immunohistochemistry, and glycosaminoglycan measurement in the supernatant. mRNA encoding type II collagen (COL2), COL10, aggrecan, and SOX5, 6, and 9 were greatly elevated already at day 7, whereas COL1 and versican mRNA were gradually reduced. COL2 and aggrecan were dispersed throughout the extracellular matrix at day 21, whereas COL10 distribution was mainly intra/ pericellular. COL1 seemed to be produced by only some of the cells. SOX proteins were predominantly localized in the nuclei. Then, using microarray analysis, we identified a signature cluster of extracellular matrix and transcription factor genes upregulated during chondrogenesis similar to COL2A1, and clusters of genes involved in immune responses, blood vessel development, and cell adhesion downregulated similar to the chemokine CXCL12. Analysis of the signature chondrogenic clusters, including novel potential marker genes identified here, may provide a better understanding of how the stem cell fate could be directed to produce perfect hyaline cartilage implants.

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“…PAPSS2 mutation results in dwarfing phenotypes (spondyloepimetaphyseal dysplasia and brachymorphism) while PAPSS1 mutation most likely results in lethality [113,119]. Recent reports suggest cartilage formation in immature guinea pigs and mice (and likely humans) is dependent on the robust expression of PAPSS2 for normal development, even though mature animals' cartilage predominantly expresses PAPSS1 [116,120]. Together, these reports support a role for PAPSS2 in the normal development of cartilage through the modulation of glycosaminoglycan sulfation, whereas PAPSS1 is the predominant isoform responsible for maintaining basal PAPS levels in most tissues throughout the body.…”

Section: The Contribution Of Paps Tissue Levels To Sult Activitymentioning

confidence: 99%

Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis

Tibbs

Rohn-Glowacki

Crittenden

et al. 2015

Drug Metabolism and Pharmacokinetics

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Expression profile of Papss2 (3′‐phosphoadenosine 5′‐phosphosulfate synthase 2) during cartilage formation and skeletal development in the mouse embryo

Abstract: Sulfation of proteoglycans is a very important

Cited by 55 publications

References 22 publications

Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate

Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate

Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells in Self-Gelling Alginate Discs Reveals Novel Chondrogenic Signature Gene Clusters

Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis

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