Evidence for osteocyte regulation of bone homeostasis through RANKL expression
Abstract
Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.
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In the initiation phase, under RANKL and M-CSF, hematopoietic stem cells are recruited to specific bone surface areas and differentiate into mature osteoclasts that initiate bone resorption.
“In the initiation phase, under the action of osteoclastogenic factors including RANKL and M-CSF, hematopoietic stem cells are recruited to specific bone surface areas and differentiate into mature osteoclasts that initiate bone resorption [167, 168].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [167]
Osteocytes act as the main source of RANKL to promote osteoclastogenesis.
“There is evidence that osteocytes act as the main source of RANKL to promote osteoclastogenesis [167, 168], although this factor has also been demonstrated to be produced by other cell types such as stromal cells [194], osteoblasts, and fibroblasts [88, 89].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [167]
Conditional deletion of RANKL expression in osteocytes using a DMP1 promoter caused a severe osteopetrotic phenotype.
“In 2011, Nakashima et al.51 showed that the conditional deletion of RANKL expression in osteocytes using a DMP1 promoter caused a severe osteopetrotic phenotype.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [51]
Osteoclast fusion requires RANKL, which is highly expressed by BLCs, osteoblasts in the growing skeleton, and osteocyte arborizations that reach the bone surface in adults.
“Fusion also requires RANKL, which is highly expressed by BLCs;161 osteoblasts in the growing skeleton; and osteocyte arborizations that reach the bone surface in adults.51,52”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [51]
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- Authors
- Nakashima, T., Hayashi, M., Fukunaga, T., Kurata, K., Oh-hora, M., Feng, J. Q., Bonewald, L. F., Kodama, T., Wutz, A., Wagner, E. F., Penninger, J. M., & Takayanagi, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Kyushu University (JP)
- Texas A&M Health Science Center (US)
- University of Missouri–Kansas City (US)
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Spanish National Cancer Research Centre (ES)
- Institute of Molecular Biotechnology (AT)
- Corresponding author
- Takayanagi, Hiroshi
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-09-11
- Volume
- 17
- Issue
- 10
- Pages
- 1231-1234
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1982395713
- Cited by
- 1,778
- References
- 20
- Citations by year
- 2026: 77 · 2025: 91 · 2024: 90 · 2023: 131 · 2022: 122 · 2021: 146 · 2020: 158 · 2019: 118 · 2018: 95 · 2017: 129 · 2016: 116 · 2015: 128 · 2014: 122 · 2013: 117 · 2012: 119
- FWCI
- 48.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (087530)
- Japan Society for the Promotion of Science (23590565)
- 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
- osteocytes, RANKL, bone homeostasis, bone remodeling, osteoclastogenesis, osteoporosis, osteoblasts, osteoclasts, osteopetrotic mice
- MeSH terms
- Animals, Bone and Bones, Cell Differentiation, Femur, Flow Cytometry, Homeostasis, Immunohistochemistry, Mice, Transgenic, Osteoclasts, Osteocytes, Osteopetrosis, Gene Expression Profiling, Green Fluorescent Proteins, Mice, RANK Ligand, X-Ray Microtomography, Real-Time Polymerase Chain Reaction
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