title: Sim1 inhibits bone formation by enhancing the sympathetic tone in male mice.
abstract: Single-minded 1 (Sim1) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that is important for neuronal development in the hypothalamus. Loss-of-function mutation of Sim1 causes early-onset obesity. However, it is unknown whether and how Sim1 regulates bone remodeling. In this study, we found that adult-onset Sim1 deletion increases bone formation, leading to high bone mass. In contrast, Sim1-overexpressing transgenic mice exhibit decreased bone formation and low bone mass. Sim1 does not directly regulate osteoblastogenesis, because bone marrow mesenchymal stem cells from Sim1 mutant mice display a normal capacity for osteoblast differentiation. Instead, Sim1 inhibits bone formation via stimulating the sympathetic nervous system, because sympathetic tone is decreased by Sim1 deletion but increased by Sim1 overexpression. Treatment with the β-adrenergic agonist isoproterenol effectively reverses the high bone mass in Sim1-knockout mice. These findings reveal Sim1 as a critical yet previously unrecognized modulator of skeletal homeostasis that functions through a central relay.
authors.affiliation: Departments of Pharmacology (X.W., W.W., Y.W.) and Internal Medicine (A.R.Z.) and Eugene McDermott Center for Human Growth and Development (A.R.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Xunde
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Zinn
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C101750:Sim1 protein, mouse