title: Matrilin-3 chondrodysplasia mutations cause attenuated chondrogenesis, premature hypertrophy and aberrant response to TGF-β in chondroprogenitor cells.
abstract: Studies have shown that mutations in the matrilin-3 gene (MATN3) are associated with multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). We tested whether MATN3 mutations affect the differentiation of chondroprogenitor and/or mesenchymal stem cells, which are precursors to chondrocytes. ATDC5 chondroprogenitors stably expressing wild-type (WT) MATN3 underwent spontaneous chondrogenesis. Expression of chondrogenic markers collagen II and aggrecan was inhibited in chondroprogenitors carrying the MED or SEMD MATN3 mutations. Hypertrophic marker collagen X remained attenuated in WT MATN3 chondroprogenitors, whereas its expression was elevated in chondroprogenitors expressing the MED or SEMD mutant MATN3 gene suggesting that these mutations inhibit chondrogenesis but promote hypertrophy. TGF-β treatment failed to rescue chondrogenesis markers but dramatically increased collagen X mRNA expression in mutant MATN3 expressing chondroprogenitors. Synovium derived mesenchymal stem cells harboring the SEMD mutation exhibited lower glycosaminoglycan content than those of WT MATN3 in response to TGF-β. Our results suggest that the properties of progenitor cells harboring MATN3 chondrodysplasia mutations were altered, as evidenced by attenuated chondrogenesis and premature hypertrophy. TGF-β treatment failed to completely rescue chondrogenesis but instead induced hypertrophy in mutant MATN3 chondroprogenitors. Our data suggest that chondroprogenitor cells should be considered as a potential target of chondrodysplasia therapy.
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 402A, 1 Hoppin Street, Providence, RI 02903, USA. chathuraka_jayasuriya@brown.edu.
authors.forename: Chathuraka T
authors.initials: CT
authors.lastname: Jayasuriya
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 402A, 1 Hoppin Street, Providence, RI 02903, USA. fiona.zhou@unisa.edu.au.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Zhou
authors.affiliation: Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University, Morgantown, WV 26506, USA. mpei@hsc.wvu.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Pei
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 402A, 1 Hoppin Street, Providence, RI 02903, USA. zwang@chartercare.org.
authors.forename: Zhengke
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 402A, 1 Hoppin Street, Providence, RI 02903, USA. nicholas_lemme@brown.edu.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lemme
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 402A, 1 Hoppin Street, Providence, RI 02903, USA. phaines@bu.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Haines
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 402A, 1 Hoppin Street, Providence, RI 02903, USA. qian_chen@brown.edu.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D020219:Chondrogenesis / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D064235:Matrilin Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D064235:Matrilin Proteins; D016212:Transforming Growth Factor beta