Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3.
Genetic mutations that disrupt osteoblast function can result in skeletal dysmorphogenesis or, more rarely, in increased postnatal bone formation. Here we show that Schnurri-3 (Shn3), a mammalian homolog of the Drosophila zinc finger adapter protein Shn, is an essential regulator of adult bone formation. Mice lacking Shn3 display adult-onset osteosclerosis with increased bone mass due to augmented osteoblast activity. Shn3 was found to control protein levels of Runx2, the principal transcriptional regulator of osteoblast differentiation, by promoting its degradation through recruitment of the E3 ubiquitin ligase WWP1 to Runx2. By this means, Runx2-mediated extracellular matrix mineralization was antagonized, revealing an essential role for Shn3 as a central regulator of postnatal bone mass.
Jones
Dallas C
DC
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Wein
Marc N
MN
Oukka
Mohamed
M
Hofstaetter
Jochen G
JG
Glimcher
Melvin J
MJ
Glimcher
Laurie H
LH
D000818:Animals; D001665:Binding Sites; D015519:Bone Density; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000737:chemistry / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D051379:Mice; D010006:Osteoblasts / Q000737:chemistry / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D010012:Osteogenesis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism; D016335:Zinc Fingers
D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C493716:Runx2 protein, mouse; C510834:Schnurri-3 protein, mouse; D025801:Ubiquitin; C510836:WWP1 protein, mouse; D044767:Ubiquitin-Protein Ligases