{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:06:26Z","timestamp":1790820386389,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2011,1,5]],"date-time":"2011-01-05T00:00:00Z","timestamp":1294185600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2011,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Proteoglycans are molecules consisting of protein cores onto which sugar chains, i.e., glycosaminoglycans (GAGs) such as heparan or chondroitin sulphates, are attached. Proteoglycans are produced by nearly all cells, and once secreted they become a major component of the extracellular matrix. Cartilage is particularly rich in proteoglycans, and changes in the structure and composition of GAGs have been found in osteochondromas and osteoarthritis. The zebrafish (<jats:italic>Danio rerio<\/jats:italic>) exhibits fast development, a growth plate\u2010like organization of its craniofacial skeleton and an availability of various mutants, making it a powerful model for the study of human skeletal disorders with unknown aetiology. We analysed skeletons from five zebrafish lines with known mutations in genes involved in proteoglycan synthesis: <jats:italic>dackel<\/jats:italic> (<jats:italic>dak\/ext2<\/jats:italic>), lacking heparan sulphate; <jats:italic>hi307<\/jats:italic> (\u03b2<jats:italic>3gat3<\/jats:italic>), deficient for most GAGs; <jats:italic>pinscher<\/jats:italic> (<jats:italic>pic\/slc35b2<\/jats:italic>), presenting defective sulphation of GAGs and other molecules; <jats:italic>hi954<\/jats:italic> (<jats:italic>uxs1<\/jats:italic>), lacking Notch and most GAGs due to impaired protein xylosylation; and <jats:italic>knypek<\/jats:italic> (<jats:italic>kny\/gpc4<\/jats:italic>), missing the protein core of the Glypican\u20104 proteoglycan. Here we show that each mutant displays different phenotypes related to: (a) cartilage morphology; (b) composition of the extracellular matrix; (c) ultrastructure of the extracellular matrix; and (d) the intracellular ultrastructure of chondrocytes, proving that sulphated GAGs orchestrate the cartilage intra\u2010 and extracellular ultrastructures. The mild phenotype of the <jats:italic>hi307<\/jats:italic> mutant suggests that proteoglycans consisting of a protein core and a short sugar linker might suffice for proper chondrocyte stacking. Finally, <jats:italic>knypek<\/jats:italic> supports the involvement of Glypican\u20104 in the craniofacial phenotype of Simpson\u2013Golabi\u2013Behmel syndrome and suggests GPC4 as a modulator of the overgrowth phenotype that is associated with this syndrome and is primarily caused by a mutation in <jats:italic>GPC3<\/jats:italic>. Moreover, we speculate on the potential involvement of <jats:italic>SLC35B2<\/jats:italic>, \u03b2<jats:italic>3GAT3<\/jats:italic> and <jats:italic>UXS1<\/jats:italic> in skeletal dysplasias. This work promotes the use of zebrafish as a model of human skeletal development and associated pathologies. Copyright \u00a9 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2824","type":"journal-article","created":{"date-parts":[[2010,11,19]],"date-time":"2010-11-19T10:15:22Z","timestamp":1290161722000},"page":"531-542","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Cartilage ultrastructure in proteoglycan\u2010deficient zebrafish mutants brings to light new candidate genes for human skeletal disorders"],"prefix":"10.1002","volume":"223","author":[{"given":"Malgorzata I","family":"Wiweger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina M","family":"Avramut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos E","family":"de Andrea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans A","family":"Prins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham J","family":"Koster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimond BG","family":"Ravelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pancras CW","family":"Hogendoorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,1,5]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-009-0822-y"},{"key":"e_1_2_7_3_2","first-page":"360","volume-title":"World Health Organization Classification of Tumours. 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