Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone
Open accessAbstract
The cytokine receptor activator of nuclear factor kappa B ligand (RANKL), encoded by the Tnfsf11 gene, is essential for osteoclastogenesis and previous studies have shown that deletion of the Tnfsf11 gene using a Dmp1-Cre transgene reduces osteoclast formation in cancellous bone by more than 70%. However, the Dmp1-Cre transgene used in those studies leads to recombination in osteocytes, osteoblasts, and lining cells making it unclear whether one or more of these cell types produce the RANKL required for osteoclast formation in cancellous bone. Because osteoblasts, osteocytes, and lining cells have distinct locations and functions, distinguishing which of these cell types are sources of RANKL is essential for understanding the orchestration of bone remodeling. To distinguish between these possibilities, we have now created transgenic mice expressing the Cre recombinase under the control of regulatory elements of the Sost gene, which is expressed in osteocytes but not osteoblasts or lining cells in murine bone. Activity of the Sost-Cre transgene in osteocytes, but not osteoblast or lining cells, was confirmed by crossing Sost-Cre transgenic mice with tdTomato and R26R Cre-reporter mice, which express tdTomato fluorescent protein or LacZ, respectively, only in cells expressing the Cre recombinase or their descendants. Deletion of the Tnfsf11 gene in Sost-Cre mice led to a threefold decrease in osteoclast number in cancellous bone and increased cancellous bone mass, mimicking the skeletal phenotype of mice in which the Tnfsf11 gene was deleted using the Dmp1-Cre transgene. These results demonstrate that osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling cancellous bone.
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Conditional deletion of RANKL expression under the more specific SOST promoter generated a phenotype resembling the previous one, with a significant decrease in osteoclasts number in cancellous bone.
“As the activation of Dmp1-Cre promoters is not exclusive to osteocytes,53 the conditional deletion of RANKL expression was performed under the control of the more specific SOST promoter. This conditional deletion generated a phenotype resembling the previous one, with a significant decrease in osteoclasts number in cancellous bone.54”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [54]
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- Authors
- Xiong, J., Piemontese, M., Onal, M., Campbell, J., Goellner, J. J., Dusevich, V., Bonewald, L., Manolagas, S. C., & O’Brien, C. A.
- Affiliations
- Central Arkansas Veterans Healthcare System (US)
- University of Missouri–Kansas City (US)
- Corresponding author
- O’Brien, Charles A.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-09-22
- Volume
- 10
- Issue
- 9
- Pages
- e0138189
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4578942
- OpenAlex
- W2195625763
- Cited by
- 323
- References
- 37
- Citations by year
- 2026: 20 · 2025: 19 · 2024: 28 · 2023: 44 · 2022: 29 · 2021: 28 · 2020: 40 · 2019: 35 · 2018: 26 · 2017: 31 · 2016: 21 · 2015: 1 · 2014: 1
- FWCI
- 11.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000294)
- National Institutes of Health (RR029884, AG13918)
- Translational Research Institute, University of Arkansas for Medical Sciences (RR029884, UL1 RR029884)
- National Institute on Aging (AG13918, P01AG013918)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR049794, R01AR049794)
- National Center for Research Resources (UL1RR029884)
- 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
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- RANKL, osteocytes, osteoclastogenesis, bone remodeling, osteoblasts, bone lining cells, trabecular bone, bone mass
- MeSH terms
- Animals, Cell Division, Mice, Transgenic, Osteoblasts, Osteoclasts, Osteocytes, Recombination, Genetic, Bone Density, Bone Remodeling, Mice, RANK Ligand
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