Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass
| Autor: | Ryan E. Tomlinson, Marie Claude Faugere, Angelica J. Herrera, Brian C. Goh, Vandana Singhal, Se-Jin Lee, Douglas J. DiGirolamo, Thomas L. Clemens, Emily L. Germain-Lee, Soo-Hyun Kim |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Activin Receptors Type II Mice Transgenic Muscle Development Osteocytes Biochemistry 03 medical and health sciences Osteogenesis Internal medicine TGF beta signaling pathway medicine Animals Femur Muscle Skeletal Molecular Biology ACVR1B Cells Cultured Crosses Genetic Activin Receptor Type-2A Activin type 2 receptors Cell Proliferation Bone Development Osteoblasts Chemistry Skull Osteoblast Cell Biology Activin receptor Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Animals Newborn Organ Specificity Mutation Female Gene Deletion ACVR2B ACVR2A |
| Zdroj: | Journal of Biological Chemistry. 292:13809-13822 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m117.782128 |
| Popis: | Bone and skeletal muscle mass are highly correlated in mammals, suggesting the existence of common anabolic signaling networks that coordinate the development of these two anatomically adjacent tissues. The activin signaling pathway is an attractive candidate to fulfill such a role. Here, we generated mice with conditional deletion of activin receptor (ACVR) type 2A, ACVR2B, or both, in osteoblasts, to determine the contribution of activin receptor signaling in regulating bone mass. Immunohistochemistry localized ACVR2A and ACVR2B to osteoblasts and osteocytes. Primary osteoblasts expressed activin signaling components, including ACVR2A, ACVR2B, and ACVR1B (ALK4) and demonstrated increased levels of phosphorylated Smad2/3 upon exposure to activin ligands. Osteoblasts lacking ACVR2B did not show significant changes in vitro. However, osteoblasts deficient in ACVR2A exhibited enhanced differentiation indicated by alkaline phosphatase activity, mineral deposition, and transcriptional expression of osterix, osteocalcin, and dentin matrix acidic phosphoprotein 1. To investigate activin signaling in osteoblasts in vivo, we analyzed the skeletal phenotypes of mice lacking these receptors in osteoblasts and osteocytes (osteocalcin-Cre). Similar to the lack of effect in vitro, ACVR2B-deficient mice demonstrated no significant change in any bone parameter. By contrast, mice lacking ACVR2A had significantly increased femoral trabecular bone volume at 6 weeks of age. Moreover, mutant mice lacking both ACVR2A and ACVR2B demonstrated sustained increases in trabecular bone volume, similar to those in ACVR2A single mutants, at 6 and 12 weeks of age. Taken together, these results indicate that activin receptor signaling, predominantly through ACVR2A, directly and negatively regulates bone mass in osteoblasts. |
| Databáze: | OpenAIRE |
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