{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:49:09Z","timestamp":1761061749179,"version":"3.41.2"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T00:00:00Z","timestamp":1670284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>Mucopolysaccharidosis type VI (MPS VI) is a metabolic disorder caused by disease-associated variants in the Arylsulfatase B (<jats:italic>ARSB<\/jats:italic>) gene, resulting in ARSB enzyme deficiency, lysosomal glycosaminoglycan accumulation, and cartilage and bone pathology. The molecular response to MPS VI that results in cartilage pathology in human patients is largely unknown. Here, we generated a disease model to study the early stages of cartilage pathology in MPS VI. We generated iPSCs from four patients and isogenic controls by inserting the <jats:italic>ARSB<\/jats:italic> cDNA in the <jats:italic>AAVS1<\/jats:italic> safe harbor locus using CRISPR\/Cas9. Using an optimized chondrogenic differentiation protocol, we found Periodic acid\u2013Schiff positive inclusions in hiPSC-derived chondrogenic cells with MPS VI. Genome-wide mRNA expression analysis showed that hiPSC-derived chondrogenic cells with MPS VI downregulated expression of genes involved in TGF-\u03b2\/BMP signalling, and upregulated expression of inhibitors of the Wnt\/\u03b2-catenin signalling pathway. Expression of genes involved in apoptosis and growth was upregulated, while expression of genes involved in glycosaminoglycan metabolism was dysregulated in hiPSC-derived chondrogenic cells with MPS VI. These results suggest that human <jats:italic>ARSB<\/jats:italic> deficiency in MPS VI causes changes in the transcriptional program underlying the early stages of chondrogenic differentiation and metabolism.<\/jats:p>","DOI":"10.3389\/fbioe.2022.949063","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T06:52:03Z","timestamp":1670309523000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Modeling cartilage pathology in mucopolysaccharidosis VI using iPSCs reveals early dysregulation of chondrogenic and metabolic gene expression"],"prefix":"10.3389","volume":"10","author":[{"given":"M.","family":"Broeders","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jgj","family":"van Rooij","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Oussoren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tjm","family":"van Gestel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ca","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sj","family":"Kimber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rm","family":"Verdijk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maem","family":"Wagenmakers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jmp","family":"van den Hout","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"At","family":"van der Ploeg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Narcisi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wwmp","family":"Pijnappel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/ncb826","article-title":"Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-\u03b2","volume":"4","author":"Abreu","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/BF00310256","article-title":"Growth plate pathology in feline mucopolysaccharidosis VI","volume":"57","author":"Abreu","year":"1995","journal-title":"Calcif. Tissue Int."},{"key":"B3","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.matbio.2014.06.001","article-title":"Cartilage oligomeric matrix protein and its binding partners in the cartilage extracellular matrix: Interaction, regulation and role in chondrogenesis","volume":"37","author":"Acharya","year":"2014","journal-title":"Matrix Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"495","DOI":"10.3390\/ijms17040495","article-title":"Wnt9A induction linked to suppression of human colorectal cancer cell proliferation","volume":"17","author":"Ali","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"129","DOI":"10.3233\/PRM-2010-0117","article-title":"Chondroitin sulfate and growth factor signaling in the skeleton: Possible links to MPS VI","volume":"3","author":"Alliston","year":"2010","journal-title":"J. Pediatr. Rehabil. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e74666","DOI":"10.1371\/journal.pone.0074666","article-title":"Nkd1 functions as a passive antagonist of Wnt signaling","volume":"8","author":"Angonin","year":"2013","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1203\/01.pdr.0000203090.41012.a6","article-title":"Intra-articular enzyme administration for joint disease in feline mucopolysaccharidosis VI: Enzyme dose and interval","volume":"59","author":"Auclair","year":"2006","journal-title":"Pediatr. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.ymgme.2007.04.009","article-title":"Long-term intra-articular administration of recombinant human N-acetylgalactosamine-4-sulfatase in feline mucopolysaccharidosis VI","volume":"91","author":"Auclair","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"B9","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/j.bbamcr.2008.12.001","article-title":"Lysosomal disorders: From storage to cellular damage","volume":"1793","author":"Ballabio","year":"2009","journal-title":"Biochimica Biophysica Acta - Mol. Cell Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/0009-8981(59)90119-6","article-title":"The assay of arylsulphatases A and B in human urine","volume":"4","author":"Baum","year":"1959","journal-title":"Clin. Chim. Acta"},{"key":"B11","doi-asserted-by":"publisher","first-page":"17022","DOI":"10.1073\/pnas.1110629108","article-title":"Modulation of canonical Wnt signaling by the extracellular matrix component biglycan","volume":"108","author":"Berendsen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B12","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1080\/19336950.2015.1116652","article-title":"Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells","volume":"10","author":"Bertram","year":"2016","journal-title":"Channels (Austin)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1002\/art.11248","article-title":"Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro","volume":"48","author":"Bobacz","year":"2003","journal-title":"Arthritis Rheum."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/ng0795-330","article-title":"Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene","volume":"10","author":"Briggs","year":"1995","journal-title":"Nat. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"100789","DOI":"10.1016\/j.isci.2019.100789","article-title":"Sharpening the molecular scissors: Advances in gene-editing Technology","volume":"23","author":"Broeders","year":"2019","journal-title":"iScience"},{"key":"B17","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.omtm.2020.09.004","article-title":"A generic assay to detect aberrant ARSB splicing and mRNA degradation for the molecular diagnosis of MPS VI","volume":"19","author":"Broeders","year":"2020","journal-title":"Mol. Ther. - Methods & Clin. Dev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/cdd.2015.100","article-title":"Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner","volume":"23","author":"Causeret","year":"2016","journal-title":"Cell Death Differ."},{"key":"B19","doi-asserted-by":"publisher","first-page":"a021923","DOI":"10.1101\/cshperspect.a021923","article-title":"Agonists and antagonists of TGF-beta family ligands","volume":"8","author":"Chang","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1080\/08977190802291733","article-title":"Effects induced by BMPS in cultures of human articular chondrocytes: Comparative studies","volume":"26","author":"Chubinskaya","year":"2008","journal-title":"Growth factors."},{"key":"B21","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.matbio.2017.12.014","article-title":"Mutant cartilage oligomeric matrix protein (COMP) compromises bone integrity, joint function and the balance between adipogenesis and osteogenesis","volume":"67","author":"Coustry","year":"2018","journal-title":"Matrix Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"a015081","DOI":"10.1101\/cshperspect.a015081","article-title":"Secreted and transmembrane wnt inhibitors and activators","volume":"5","author":"Cruciat","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1007\/s00018-009-8632-6","article-title":"Fibulins: Multiple roles in matrix structures and tissue functions","volume":"66","author":"de Vega","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"Star: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1016\/s0021-9290(01)00156-7","article-title":"Hyper-osmotic stress induces volume change and calcium transients in chondrocytes by transmembrane, phospholipid, and G-protein pathways","volume":"34","author":"Erickson","year":"2001","journal-title":"J. Biomech."},{"key":"B26","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1053\/s1063-4584(02)00347-3","article-title":"Hypo-osmotic stress induces calcium-dependent actin reorganization in articular chondrocytes","volume":"11","author":"Erickson","year":"2003","journal-title":"Osteoarthr. Cartil."},{"key":"B27","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/j.omtm.2020.06.022","article-title":"Ready for repair? Gene editing enters the clinic for the treatment of human disease","volume":"18","author":"Ernst","year":"2020","journal-title":"Mol. Ther. - Methods & Clin. Dev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"8214","DOI":"10.1073\/pnas.93.16.8214","article-title":"Targeted disruption of the arylsulfatase B gene results in mice resembling the phenotype of mucopolysaccharidosis VI","volume":"93","author":"Evers","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1838","DOI":"10.3390\/cells9081838","article-title":"Mucopolysaccharidosis type I: A review of the natural history and molecular pathology","volume":"9","author":"Hampe","year":"2020","journal-title":"Cells"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1101\/gr.135350.111","article-title":"Gencode: The reference human genome annotation for the ENCODE project","volume":"22","author":"Harrow","year":"2012","journal-title":"Genome Res."},{"key":"B31","first-page":"657","article-title":"The pathology of the feline model of mucopolysaccharidosis VI","volume":"101","author":"Haskins","year":"1980","journal-title":"Am. J. Pathol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/s0945-053x(98)90080-4","article-title":"Characterization of cartilage oligomeric matrix protein (COMP) in human normal and pseudochondroplasia musculoskeletal tissues","volume":"17","author":"Hecht","year":"1998","journal-title":"Matrix Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.matbio.2004.09.006","article-title":"COMP mutations, chondrocyte function and cartilage matrix","volume":"23","author":"Hecht","year":"2005","journal-title":"Matrix Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/ng0795-325","article-title":"Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia","volume":"10","author":"Hecht","year":"1995","journal-title":"Nat. Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1096\/fj.05-3875com","article-title":"Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: Mutual cross inhibition with indoleamine 2, 3-dioxygenase","volume":"19","author":"Hill","year":"2005","journal-title":"FASEB J."},{"key":"B36","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/j.stem.2016.04.013","article-title":"Induced pluripotent stem cells meet genome editing","volume":"18","author":"Hockemeyer","year":"2016","journal-title":"Cell Stem Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.tibs.2008.07.006","article-title":"The CCN family of proteins: Structure-function relationships","volume":"33","author":"Holbourn","year":"2008","journal-title":"Trends biochem. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2373","DOI":"10.1242\/dev.128.12.2373","article-title":"Msx homeobox genes inhibit differentiation through upregulation of cyclin D1","volume":"128","author":"Hu","year":"2001","journal-title":"Development"},{"key":"B39","doi-asserted-by":"publisher","first-page":"7525","DOI":"10.1111\/jcmm.14621","article-title":"NOV\/CCN3 induces cartilage protection by inhibiting PI3K\/AKT\/mTOR pathway","volume":"23","author":"Huang","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3683","DOI":"10.1083\/jcb.201709149","article-title":"Draxin acts as a molecular rheostat of canonical Wnt signaling to control cranial neural crest EMT","volume":"217","author":"Hutchins","year":"2018","journal-title":"J. Cell Biol."},{"key":"B86","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/978-1-0716-1657-4_16","article-title":"CRISPR-Cas9-Mediated gene editing in human induced pluripotent stem cells","volume-title":"CRISPR-cas methods: Volume 2","author":"in \u2019t Groen","year":"2021"},{"key":"B41","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1007\/s00774-016-0793-4","article-title":"Novel role of CCN3 that maintains the differentiated phenotype of articular cartilage","volume":"35","author":"Janune","year":"2017","journal-title":"J. Bone Min. Metab."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1128\/mcb.22.4.1172-1183","article-title":"Wnt\/\u03b2-Catenin\/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway","volume":"22","author":"Jho","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"115195","DOI":"10.1016\/j.bone.2019.115195","article-title":"Cell cycle progression is disrupted in murine MPS VII growth plate leading to reduced chondrocyte proliferation and transition to hypertrophy","volume":"132","author":"Jiang","year":"2020","journal-title":"Bone"},{"key":"B44","doi-asserted-by":"publisher","first-page":"4042","DOI":"10.1158\/1078-0432.CCR-06-2316","article-title":"WNT signaling pathway and stem cell signaling network","volume":"13","author":"Katoh","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"C1387","DOI":"10.1152\/ajpcell.00346.2007","article-title":"Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity","volume":"294","author":"Khan","year":"2008","journal-title":"Am. J. Physiology-Cell Physiology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/s0898-6568(99)00054-6","article-title":"Roles of axin in the wnt signalling pathway","volume":"11","author":"Kikuchi","year":"1999","journal-title":"Cell. Signal."},{"key":"B47","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1593\/neo.101540","article-title":"Imaging bone morphogenetic protein 7 induced cell cycle arrest in experimental gliomas","volume":"13","author":"Klose","year":"2011","journal-title":"Neoplasia"},{"key":"B48","doi-asserted-by":"publisher","first-page":"3989","DOI":"10.1242\/dev.01948","article-title":"Maintenance of chondroitin sulfation balance by chondroitin-4-sulfotransferase 1 is required for chondrocyte development and growth factor signaling during cartilage morphogenesis","volume":"132","author":"Kluppel","year":"2005","journal-title":"Development"},{"key":"B49","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1093\/jb\/mvv124","article-title":"Regulation of bone metabolism by Wnt signals","volume":"159","author":"Kobayashi","year":"2016","journal-title":"J. Biochem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1038\/cdd.2014.90","article-title":"Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3","volume":"21","author":"Koenig","year":"2014","journal-title":"Cell Death Differ."},{"key":"B51","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/ar2116","article-title":"Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: Regulation of niche, self-renewal and differentiation","volume":"9","author":"Kolf","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"B52","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1124\/mol.115.098160","article-title":"The ClC-7 chloride channel is downregulated by hypoosmotic stress in human chondrocytes","volume":"88","author":"Kurita","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.ydbio.2009.04.038","article-title":"Msx genes are important apoptosis effectors downstream of the Shh\/Gli3 pathway in the limb","volume":"331","author":"Lallemand","year":"2009","journal-title":"Dev. Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1091\/mbc.E14-12-1648","article-title":"Wnt ligand-dependent activation of the negative feedback regulator Nkd1","volume":"26","author":"Larraguibel","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"B55","doi-asserted-by":"publisher","first-page":"357","DOI":"10.3389\/fphys.2015.00357","article-title":"Changes in membrane receptors and ion channels as potential biomarkers for osteoarthritis","volume":"6","author":"Lewis","year":"2015","journal-title":"Front. Physiol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"B57","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/B978-0-12-800039-7.00004-9","article-title":"Chapter 4 - cross talk between inflammation and extracellular matrix following myocardial infarction","volume-title":"Inflammation in heart failure","author":"Ma","year":"2015"},{"key":"B58","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/jb\/mvn159","article-title":"CCN family 2\/connective tissue growth factor modulates BMP signalling as a signal conductor, which action regulates the proliferation and differentiation of chondrocytes","volume":"145","author":"Maeda","year":"2009","journal-title":"J. Biochem."},{"key":"B59","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.3390\/ijms22052242","article-title":"COMP and TSP-4: Functional roles in articular cartilage and relevance in osteoarthritis","volume":"22","author":"Maly","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1038\/nature756","article-title":"Kremen proteins are Dickkopf receptors that regulate Wnt\/\u03b2-catenin signalling","volume":"417","author":"Mao","year":"2002","journal-title":"Nature"},{"key":"B61","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1002\/(sici)1096-8628(19960517)63:2<406::aid-ajmg16>3.0.co;2-o","article-title":"Natural history study of pseudoachondroplasia","volume":"63","author":"McKeand","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"B62","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/s41596-019-0128-8","article-title":"Protocol Update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0)","volume":"14","author":"Mi","year":"2019","journal-title":"Nat. Protoc."},{"key":"B63","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/msb.2009.72","article-title":"Application of an integrated physical and functional screening approach to identify inhibitors of the Wnt pathway","volume":"5","author":"Miller","year":"2009","journal-title":"Mol. Syst. Biol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1016\/j.bbrc.2009.10.113","article-title":"Neucrin is a novel neural-specific secreted antagonist to canonical Wnt signaling","volume":"390","author":"Miyake","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B65","doi-asserted-by":"publisher","first-page":"275","DOI":"10.3892\/br.2016.580","article-title":"Pleckstrin homology-like domain, family A, member 1 (PHLDA1) and cancer","volume":"4","author":"Nagai","year":"2016","journal-title":"Biomed. Rep."},{"key":"B66","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.stemcr.2015.01.017","article-title":"Long-term expansion, enhanced chondrogenic potential, and suppression of endochondral ossification of adult human MSCs via WNT signaling modulation","volume":"4","author":"Narcisi","year":"2015","journal-title":"Stem Cell Rep."},{"key":"B67","first-page":"5920","article-title":"Identification of the human PHLDA1\/TDAG51 gene: Down-regulation in metastatic melanoma contributes to apoptosis resistance and growth deregulation","volume":"62","author":"Neef","year":"2002","journal-title":"Cancer Res."},{"key":"B68","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1681\/asn.2007111261","article-title":"CTGF inhibits BMP-7 signaling in diabetic nephropathy","volume":"19","author":"Nguyen","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1038\/nbt.1683","article-title":"Directed differentiation of human embryonic stem cells toward chondrocytes","volume":"28","author":"Oldershaw","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.ymgme.2017.05.008","article-title":"A long term follow-up study of the development of hip disease in Mucopolysaccharidosis type VI","volume":"121","author":"Oussoren","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.bbadis.2011.07.013","article-title":"Bone, joint and tooth development in mucopolysaccharidoses: Relevance to therapeutic options","volume":"1812","author":"Oussoren","year":"2011","journal-title":"Biochimica Biophysica Acta - Mol. Basis Dis."},{"key":"B72","doi-asserted-by":"publisher","first-page":"115729","DOI":"10.1016\/j.bone.2020.115729","article-title":"Hip disease in mucopolysaccharidoses and mucolipidoses: A review of mechanisms, interventions and future perspectives","volume":"143","author":"Oussoren","year":"2021","journal-title":"Bone"},{"key":"B73","doi-asserted-by":"publisher","first-page":"S41","DOI":"10.1038\/onc.2009.42","article-title":"Bim and Bmf in tissue homeostasis and malignant disease","volume":"27","author":"Pinon","year":"2008","journal-title":"Oncogene"},{"key":"B74","doi-asserted-by":"publisher","first-page":"F19","DOI":"10.1152\/ajprenal.2001.280.1.F19","article-title":"BMP7 controls collecting tubule cell proliferation and apoptosis via Smad1-dependent and -independent pathways","volume":"280","author":"Piscione","year":"2001","journal-title":"Am. J. Physiology-Renal Physiology"},{"key":"B75","doi-asserted-by":"publisher","first-page":"869","DOI":"10.2174\/138945008785909293","article-title":"The role of cartilage oligomeric matrix protein (COMP) in skeletal disease","volume":"9","author":"Posey","year":"2008","journal-title":"Curr. Drug Targets"},{"key":"B76","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/cgt.2008.78","article-title":"Downregulation of Wnt2 and beta-catenin by siRNA suppresses malignant glioma cell growth","volume":"16","author":"Pu","year":"2009","journal-title":"Cancer Gene Ther."},{"key":"B77","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.joca.2006.07.005","article-title":"Effects of pleiotrophin, a heparin-binding growth factor, on human primary and immortalized chondrocytes","volume":"15","author":"Pufe","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"B78","doi-asserted-by":"publisher","first-page":"15005","DOI":"10.1038\/boneres.2015.5","article-title":"TGF-\u03b2\/BMP signaling and other molecular events: Regulation of osteoblastogenesis and bone formation","volume":"3","author":"Rahman","year":"2015","journal-title":"Bone Res."},{"key":"B79","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1038\/sj.onc.1209852","article-title":"Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis","volume":"26","author":"Ramjaun","year":"2007","journal-title":"Oncogene"},{"key":"B80","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/s41389-018-0105-z","article-title":"The extracellular SEMA domain attenuates intracellular apoptotic signaling of semaphorin 6A in lung cancer cells","volume":"7","author":"Shen","year":"2018","journal-title":"Oncogenesis"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1038\/nature08875","article-title":"APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex","volume":"464","author":"Shimomura","year":"2010","journal-title":"Nature"},{"key":"B82","doi-asserted-by":"publisher","first-page":"2955","DOI":"10.1128\/MCB.26.8.2955-2964.2006","article-title":"CCN1\/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells","volume":"26","author":"Si","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"112","DOI":"10.2353\/ajpath.2008.070564","article-title":"Mechanism of glycosaminoglycan-mediated bone and joint disease: Implications for the mucopolysaccharidoses and other connective tissue diseases","volume":"172","author":"Simonaro","year":"2008","journal-title":"Am. J. Pathol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.cell.2011.06.019","article-title":"Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations","volume":"146","author":"Soldner","year":"2011","journal-title":"Cell"},{"key":"B85","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s12026-014-8545-9","article-title":"From inception to output, Tcf1 and Lef1 safeguard development of T cells and innate immune cells","volume":"59","author":"Steinke","year":"2014","journal-title":"Immunol. Res."},{"key":"B87","doi-asserted-by":"publisher","first-page":"795","DOI":"10.3390\/ijms20040795","article-title":"Increased TGF-beta and BMP levels and improved chondrocyte-specific marker expression in vitro under cartilage-specific physiological osmolarity","volume":"20","author":"Tan Timur","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B88","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1359\/jbmr.2002.17.11.2009","article-title":"Pleiotrophin\/Osteoblast-stimulating factor 1: Dissecting its diverse functions in bone formation","volume":"17","author":"Tare","year":"2002","journal-title":"J. Bone Min. Res."},{"key":"B89","doi-asserted-by":"publisher","first-page":"969","DOI":"10.3390\/cells8090969","article-title":"TGF\u03b2\/BMP signaling pathway in cartilage homeostasis","volume":"8","author":"Thielen","year":"2019","journal-title":"Cells"},{"key":"B90","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/nrm1130","article-title":"Fibulins: A versatile family of extracellular matrix proteins","volume":"4","author":"Timpl","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1002\/ajmg.10234","article-title":"Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments","volume":"106","author":"Unger","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"B92","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/labinvest.2015.142","article-title":"Wnt signaling in cartilage development and diseases: Lessons from animal studies","volume":"96","author":"Usami","year":"2016","journal-title":"Lab. Invest."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1016\/j.stemcr.2018.04.002","article-title":"Large-Scale expansion of human iPSC-derived skeletal muscle cells for disease modeling and cell-based therapeutic strategies","volume":"10","author":"van der Wal","year":"2018","journal-title":"Stem Cell Rep."},{"key":"B94","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/B978-0-12-405943-6.00008-7","article-title":"Hey bHLH transcription factors","volume":"110","author":"Weber","year":"2014","journal-title":"Curr. Top. Dev. Biol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1002\/jor.22983","article-title":"Expression of growth differentiation factor 6 in the human developing fetal spine retreats from vertebral ossifying regions and is restricted to cartilaginous tissues","volume":"34","author":"Wei","year":"2016","journal-title":"J. Orthop. Res."},{"key":"B96","doi-asserted-by":"publisher","first-page":"6782","DOI":"10.1158\/0008-5472.CAN-09-0128","article-title":"Identification of a protein, G0S2, that lacks Bcl-2 homology domains and interacts with and antagonizes Bcl-2","volume":"69","author":"Welch","year":"2009","journal-title":"Cancer Res."},{"key":"B97","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1038\/s41419-018-1101-0","article-title":"Sialyltransferase ST3GAL1 promotes cell migration, invasion, and TGF-\u03b21-induced EMT and confers paclitaxel resistance in ovarian cancer","volume":"9","author":"Wu","year":"2018","journal-title":"Cell Death Dis."},{"key":"B98","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41413-017-0005-4","article-title":"Transforming growth factor-beta in stem cells and tissue homeostasis","volume":"6","author":"Xu","year":"2018","journal-title":"Bone Res."},{"key":"B99","doi-asserted-by":"publisher","first-page":"e0204384","DOI":"10.1371\/journal.pone.0204384","article-title":"The role of BMP6 in the proliferation and differentiation of chicken cartilage cells","volume":"14","author":"Ye","year":"2019","journal-title":"PLoS One"},{"key":"B100","doi-asserted-by":"publisher","first-page":"6170","DOI":"10.1038\/sj.onc.1207844","article-title":"Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells","volume":"23","author":"You","year":"2004","journal-title":"Oncogene"},{"key":"B101","doi-asserted-by":"publisher","first-page":"2986","DOI":"10.3892\/ijmm.2018.3468","article-title":"Homeobox protein MSX1 inhibits the growth and metastasis of breast cancer cells and is frequently silenced by promoter methylation","volume":"41","author":"Yue","year":"","journal-title":"Int. J. Mol. Med."},{"key":"B102","doi-asserted-by":"publisher","first-page":"4769","DOI":"10.2147\/OTT.S165144","article-title":"<em&gt;MSX1&lt;\/em&gt; induces G0\/G1 arrest and apoptosis by suppressing Notch signaling and is frequently methylated in cervical cancer","volume":"11","author":"Yue","year":"","journal-title":"Onco. Targets. Ther."},{"key":"B103","doi-asserted-by":"publisher","first-page":"805","DOI":"10.3892\/ijo.2017.3855","article-title":"Early growth response 3 inhibits growth of hepatocellular carcinoma cells via upregulation of Fas ligand","volume":"50","author":"Zhang","year":"2017","journal-title":"Int. J. Oncol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"5069","DOI":"10.1038\/onc.2014.429","article-title":"NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma","volume":"34","author":"Zhao","year":"2015","journal-title":"Oncogene"},{"key":"B105","doi-asserted-by":"publisher","first-page":"e69593","DOI":"10.1371\/journal.pone.0069593","article-title":"Activation of wnt\/\u03b2-catenin signaling increases apoptosis in melanoma cells treated with trail","volume":"8","author":"Zimmerman","year":"2013","journal-title":"PLoS One"},{"key":"B106","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1096\/fasebj.31.1_supplement.178.8","article-title":"Knockout of the PHLDA1 gene in breast cancer cells reveals multiple roles for PHLDA1 in cancer phenotypes","volume":"31","author":"Zimnicka","year":"2017","journal-title":"FASEB J."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2022.949063\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T06:52:07Z","timestamp":1670309527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2022.949063\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,6]]},"references-count":106,"alternative-id":["10.3389\/fbioe.2022.949063"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2022.949063","relation":{},"ISSN":["2296-4185"],"issn-type":[{"type":"electronic","value":"2296-4185"}],"subject":[],"published":{"date-parts":[[2022,12,6]]},"article-number":"949063"}}