Osteocyte Network; a Negative Regulatory System for Bone Mass Augmented by the Induction of Rankl in Osteoblasts and Sost in Osteocytes at Unloading
Open accessAbstract
Reduced mechanical stress is a major cause of osteoporosis in the elderly, and the osteocyte network, which comprises a communication system through processes and canaliculi throughout bone, is thought to be a mechanosensor and mechanotransduction system; however, the functions of osteocytes are still controversial and remain to be clarified. Unexpectedly, we found that overexpression of BCL2 in osteoblasts eventually caused osteocyte apoptosis. Osteoblast and osteoclast differentiation were unaffected by BCL2 transgene in vitro. However, the cortical bone mass increased due to enhanced osteoblast function and suppressed osteoclastogenesis at 4 months of age, when the frequency of TUNEL-positive lacunae reached 75%. In the unloaded condition, the trabecular bone mass decreased in both wild-type and BCL2 transgenic mice at 6 weeks of age, while it decreased due to impaired osteoblast function and enhanced osteoclastogenesis in wild-type mice but not in BCL2 transgenic mice at 4 months of age. Rankl and Opg were highly expressed in osteocytes, but Rankl expression in osteoblasts but not in osteocytes was increased at unloading in wild-type mice but not in BCL2 transgenic mice at 4 months of age. Sost was locally induced at unloading in wild-type mice but not in BCL2 transgenic mice, and the dissemination of Sost was severely interrupted in BCL2 transgenic mice, showing the severely impaired osteocyte network. These findings indicate that the osteocyte network is required for the upregulation of Rankl in osteoblasts and Sost in osteocytes in the unloaded condition. These findings suggest that the osteocyte network negatively regulate bone mass by inhibiting osteoblast function and activating osteoclastogenesis, and these functions are augmented in the unloaded condition at least partly through the upregulation of Rankl expression in osteoblasts and that of Sost in osteocytes, although it cannot be excluded that low BCL2 transgene expression in osteoblasts contributed to the enhanced osteoblast function.
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Mechanical unloading downregulates anabolic factors and stimulates osteocytes to produce sclerostin and DKK-1 (inhibitors of osteoblast activity) and factors that stimulate local osteoclastogenesis.
“On the other hand, mechanical unloading downregulates anabolic factors and stimulates osteocytes to produce sclerostin and DKK-1, which are inhibitors of osteoblast activity [185–188], as well as specific factors that stimulate local osteoclastogenesis [189].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [188]
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- Authors
- Moriishi, T., Fukuyama, R., Ito, M., Miyazaki, T., Maeno, T., Kawai, Y., Komori, H., & Komori, T.
- Affiliations
- Nagasaki University (JP)
- Hiroshima International University (JP)
- Osaka City University (JP)
- Corresponding author
- Komori, Toshihisa
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-06-29
- Volume
- 7
- Issue
- 6
- Pages
- e40143
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3387151
- OpenAlex
- W1964279564
- Cited by
- 105
- References
- 55
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 7 · 2021: 13 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 5 · 2016: 6 · 2015: 12 · 2014: 11 · 2013: 6
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Nagasaki University's Academic Output SITE (Nagasaki University) (submittedVersion, cc-by-nc-nd)
- Funders
- Nakatomi Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (24659829, 22249062)
- 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 › Physiology › Spaceflight effects on biology
- Keywords
- osteocyte network, osteocyte apoptosis, Bcl-2, osteoblast activity, osteoclastogenesis, RANKL, sclerostin, osteoporosis, mechanical unloading, mechanotransduction, bone mass regulation, trabecular bone, cortical bone
- MeSH terms
- Animals, Bone and Bones, Bone Resorption, Cell Count, Cell Differentiation, Glycoproteins, Humans, Immunohistochemistry, Mice, Transgenic, Models, Biological, Organ Size, Osteoblasts, Osteocytes, Osteogenesis, Up-Regulation, Apoptosis, Transgenes, Proto-Oncogene Proteins c-bcl-2, Hindlimb Suspension, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, RANK Ligand, X-Ray Microtomography, Real-Time Polymerase Chain Reaction
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