title: Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation.
abstract: In skeletal tissue, loss or mutation of the gap junction protein connexin 43 (Cx43, also known as GJA1) in cells of the osteoblast lineage leads to a profound cortical bone phenotype and defective tissue remodeling. There is mounting evidence in bone cells that the C-terminus (CT) of Cx43 is a docking platform for signaling effectors and is required for efficient downstream signaling. Here, we examined this function, using a mouse model of Cx43 CT-truncation (Gja1 K258Stop). Relative to Gja1+/-controls, male Gja1-/K258Stopmice have a cortical bone phenotype that is remarkably similar to those reported for deletion of the entire Cx43 gene in osteoblasts. Furthermore, we show that the Cx43 CT binds several signaling proteins that are required for optimal osteoblast function, including PKCδ, ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) and β-catenin. Deletion of the Cx43 CT domain affects these signaling cascades, impacting osteoblast proliferation, differentiation, and collagen processing and organization. These data imply that, at least in bone, Cx43 gap junctions not only exchange signals, but also recruit the appropriate effector molecules to the Cx43 CT in order to efficiently activate signaling cascades that affect cell function and bone acquisition.
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Moorer
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Hebert
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Tomlinson
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Shama R
authors.initials: SR
authors.lastname: Iyer
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Chason
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA jstains@som.umaryland.edu.
authors.forename: Joseph P
authors.identifier: 0000-0002-1610-4694
authors.initials: JP
authors.lastname: Stains
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption / Q000473:pathology; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D018031:Connexin 43 / Q000737:chemistry* / Q000378:metabolism*; D000071538:Cortical Bone / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D008297:Male; D051379:Mice; D023421:Models, Animal; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D010641:Phenotype; D016062:Porosity; D011485:Protein Binding; D000072417:Protein Domains; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018031:Connexin 43; D012333:RNA, Messenger; D003094:Collagen
keywords: Cx43 K258Stop; Gap junction; Intercellular communication; Osteoblast; Osteocyte; Signal transduction