Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass
Open accessAbstract
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.
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Systemic administration of ACVR2B/Fc can lead to significant increases in bone density.
“Moreover, because this decoy receptor can block not only MSTN but also activin A, systemic administration of ACVR2B/Fc can also lead to significant increases in bone density (18–20).”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [20]
The section “Soluble activin type II receptors increase bone mass in vivo and osteoblast differentiation in vitro” reports that systemic ACVR2B/Fc injections in mice nearly tripled trabecular bone volume and significantly increased calvarial bone volume. It does not report a bone-density measurement, so the claimed increase in density is not directly established by these results. (LLM, conf=0.82)
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- Authors
- Goh, B. C., Singhal, V., Herrera, A. J., Tomlinson, R. E., Kim, S., Faugere, M.-C., Germain-Lee, E. L., Clemens, T. L., Lee, S.-J., & DiGirolamo, D. J.
- Affiliations
- United States Department of Veterans Affairs (US)
- Johns Hopkins University (US)
- Corresponding author
- DiGirolamo, Douglas J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 292
- Issue
- 33
- Pages
- 13809-13822
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5566533
- OpenAlex
- W2729094506
- Cited by
- 63
- References
- 63
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 13 · 2020: 9 · 2019: 6 · 2018: 7 · 2017: 2 · 2016: 1
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062074, R01AR060636)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- ACVR2B, activin signaling, osteoblasts, bone mass regulation, trabecular bone volume, osteogenic differentiation, Smad2/3 phosphorylation, osteocytes, conditional knockout mice
- MeSH terms
- Animals, Animals, Newborn, Bone Development, Cells, Cultured, Crosses, Genetic, Female, Femur, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Organ Specificity, Osteoblasts, Osteocytes, Osteogenesis, Skull, Gene Deletion, Muscle, Skeletal, Muscle Development, Activin Receptors, Type II, Cell Proliferation
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