title: Targeted deletion of Sost distal enhancer increases bone formation and bone mass.
abstract: The Wnt antagonist Sost has emerged as a key regulator of bone homeostasis through the modulation of Lrp4/5/6 Wnt coreceptors. In humans, lack of Sclerostin causes sclerosteosis and van Buchem (VB) disease, two generalized skeletal hyperostosis disorders that result from hyperactive Wnt signaling. Unlike sclerosteosis, VB patients lack SOST coding mutations but carry a homozygous 52 kb noncoding deletion that is essential for the transcriptional activation of SOST in bone. We recently identified a putative bone enhancer, ECR5, in the VB deletion region, and showed that the transcriptional activity of ECR5 is controlled by Mef2C transcription factor in vitro. Here we report that mice lacking ECR5 or Mef2C through Col1-Cre osteoblast/osteocyte-specific ablation result in high bone mass (HBM) due to elevated bone formation rates. We conclude that the absence of the Sost-specific long-range regulatory element ECR5 causes VB disease in rodents, and that Mef2C is the main transcription factor responsible for ECR5-dependent Sost transcriptional activation in the adult skeleton.
authors.affiliation: Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, CA 94550, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Collette
authors.forename: Damian C
authors.initials: DC
authors.lastname: Genetos
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.forename: LiQin
authors.initials: L
authors.lastname: Xie
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahnazari
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.forename: Richard M
authors.initials: RM
authors.lastname: Harland
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D000818:Animals; D016723:Bone Remodeling / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D005269:Femur / Q000166:cytology / Q000502:physiology; D017353:Gene Deletion; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D015576:Hyperostosis / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007763:Lac Operon; D064326:MEF2 Transcription Factors; D008297:Male; D008334:Mandible / Q000002:abnormalities / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D010009:Osteochondrodysplasias; D010011:Osteocytes / Q000502:physiology*; D010026:Osteosclerosis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012886:Skull / Q000002:abnormalities / Q000378:metabolism; D013576:Syndactyly / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; C486030:Sost protein, mouse