Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation
Abstract
Bone remodeling is achieved through the coupled activities of osteoclasts and osteoblasts that are controlled by many locally generated secreted factors, including WNT5A. While previous studies have demonstrated that osteoblast‐derived WNT5A promotes osteoclastogenesis, the function of osteoclast‐derived WNT5A on bone remodeling has remained unexplored. We examined the effects of osteoclast‐derived WNT5A on bone homeostasis by utilizing the Cathepsin K‐Cre (Ctsk‐Cre) mouse to conditionally delete Wnt5a in mature osteoclasts. These mice exhibited reduced trabecular and cortical bone. The low bone–mass phenotype was driven by decreased bone formation, not osteoclast‐mediated bone resorption, as osteoclast number and serum CTX marker were unchanged. Furthermore, molecular analysis of osteoclast‐ and osteoblast‐derived WNT5A identified a serine‐phosphorylated WNT5A that is unique to RANKL‐treated macrophages mimicking osteoclasts. This study suggests a new paradigm in which WNT5A has opposing effects on bone remodeling that are dependent on the cell of origin, an effect that may result from cell type–specific differential posttranslational modifications of WNT5A.
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Deletion of the phosphorylated form of WNT5a in mature osteoclasts led to reduced bone formation in male mice.
“Furthermore, deletion of this phosphorylated form of WNT5a in mature osteoclasts led to reduced bone formation in male mice.184”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [184]
After RANKL stimulation, osteoclast precursors produce and secrete a unique phosphorylated form of WNT5A.
“after RANKL stimulation, osteoclast precursors also produce and secrete a unique phosphorylated form of WNT5A.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [184]
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- Authors
- Roberts, J. L., Liu, G., Paglia, D. N., Kinter, C. W., Fernandes, L. M., Lorenzo, J., Hansen, M. F., Arif, A., & Drissi, H.
- Affiliations
- Emory University (US)
- Rutgers, The State University of New Jersey (US)
- UConn Health (US)
- Corresponding author
- Drissi, Hicham
- ORCID
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2020-01-09
- Volume
- 1463
- Issue
- 1
- Pages
- 45-59
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- OpenAlex
- W2998847167
- Cited by
- 32
- References
- 49
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 6
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (R01AR063661, R21 AR057990‐01)
- Emory University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- Wnt5a, osteoclasts, bone remodeling, bone loss, bone formation, serine phosphorylation, RANKL, trabecular bone, cortical bone, bone homeostasis, post-translational modification
- MeSH terms
- RAW 264.7 Cells, Wnt-5a Protein, Animals, Bone Resorption, Male, Mice, Inbred C57BL, Mice, Transgenic, Osteoclasts, Osteogenesis, Gene Deletion, Mice, Knockout, Mice
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