title: Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a.
abstract: Trisomy 21 causes skeletal alterations in individuals with Down syndrome (DS), but the causative trisomic gene and a therapeutic approach to rescue these abnormalities are unknown. Individuals with DS display skeletal alterations including reduced bone mineral density, modified bone structure and distinctive facial features. Due to peripheral skeletal anomalies and extended longevity, individuals with DS are increasingly more susceptible to bone fractures. Understanding the genetic and developmental origin of DS skeletal abnormalities would facilitate the development of therapies to rescue these and other deficiencies associated with DS. DYRK1A is found in three copies in individuals with DS and Ts65Dn DS mice and has been hypothesized to be involved in many Trisomy 21 phenotypes including skeletal abnormalities. Return of Dyrk1a copy number to normal levels in Ts65Dn mice rescued the appendicular bone abnormalities, suggesting that appropriate levels of DYRK1A expression are critical for the development and maintenance of the DS appendicular skeleton. Therapy using the DYRK1A inhibitor epigallocatechin-3-gallate improved Ts65Dn skeletal phenotypes. These outcomes suggest that the osteopenic phenotype associated with DS may be rescued postnatally by targeting trisomic Dyrk1a.
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, Indianapolis, IN 46202, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Blazek
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, Indianapolis, IN 46202, USA.
authors.forename: Irushi
authors.initials: I
authors.lastname: Abeysekera
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, Indianapolis, IN 46202, USA rjroper@iupui.edu.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Roper
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy / Q000235:genetics*; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D018628:Gene Dosage; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000097603:Dyrk Kinases
chemical_list: D002392:Catechin; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C045651:epigallocatechin gallate