Defective signaling, osteoblastogenesis, and bone remodeling in a mouse model of connexin43 C-terminal truncation
| Autor: | Shama R. Iyer, Carla Hebert, Joseph P. Stains, Ryan E. Tomlinson, Megan C. Moorer, Max Chason |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Connexin Biology Bone remodeling Mice 03 medical and health sciences Calcification Physiologic Protein Domains Osteogenesis Bone cell Cortical Bone medicine Animals RNA Messenger Bone Resorption Cell Proliferation Genetics Osteoblasts Gap junction Cell Differentiation Osteoblast Cell Biology Extracellular Matrix Cell biology Phenotype 030104 developmental biology medicine.anatomical_structure Connexin 43 Osteocyte Models Animal cardiovascular system Cortical bone Bone Remodeling Collagen sense organs biological phenomena cell phenomena and immunity Signal transduction Porosity Protein Binding Signal Transduction Research Article |
| Zdroj: | Journal of Cell Science. |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.197285 |
| Popis: | 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−/K258Stop mice 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|