Year: 2013
Type: article
Abstract: Mice deficient in Schnurri-3 (SHN3; also known as HIVEP3) display increased bone formation, but harnessing this observation for therapeutic benefit requires an improved understanding of how SHN3 functions in osteoblasts. Here we identified SHN3 as a dampener of ERK activity that functions in part downstream of WNT signaling in osteoblasts. A D-domain motif within SHN3 mediated the interaction with and inhibition of ERK activity and osteoblast differentiation, and knockin of a mutation in Shn3 that abolishes this interaction resulted in aberrant ERK activation and consequent osteoblast hyperactivity in vivo. Additionally, in vivo genetic interaction studies demonstrated that crossing to Lrp5(-/-) mice partially rescued the osteosclerotic phenotype of Shn3(-/-) mice; mechanistically, this corresponded to the ability of SHN3 to inhibit ERK-mediated suppression of GSK3β. Inducible knockdown of Shn3 in adult mice resulted in a high-bone mass phenotype, providing evidence that transient blockade of these pathways in adults holds promise as a therapy for osteoporosis.
DOI: 10.1172/jci69443
Institutions: Weill Cornell Medicine, Brigham and Women's Hospital, Shanghai Institutes for Biological Sciences, Center for Excellence in Molecular Cell Science, Harbin Institute of Technology, Massachusetts General Hospital, University of Minnesota, Masonic Cancer Center, Université Laval, Brandeis University, Merck & Co., Inc., Rahway, NJ, USA (United States), Harvard University
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Arthritis Foundation, Dana-Farber Cancer Institute, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W2052749742