Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling
Open accessAbstract
Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRII ocy−/− ), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.
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Deterioration of the lacuno-canalicular network was accompanied by a decrease in the gene expression of Sost and metalloproteases Mmp2, 13, 14, and by reduction of fracture resistance in cortical bone despite no differences in cortical thickness and geometry, and increase in trabecular bone mass, likely due to the observed decrease in osteoclasts number and surface.
“The deterioration of the lacuno-canalicular network was accompanied by the decrease in the gene expression of Sost, and metalloproteases Mmp2, 13, 14, which are involved in the lacuno-canalicular remodeling, and by the reduction of fracture resistance in cortical bone despite no differences in cortical thickness and geometry, and increase in trabecular bone mass, likely due to the observed”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [98]
The observation that lacuno-canalicular remodeling is an essential component of bone mechanical competence sustains the view that osteocytes play an evolutionarily conserved role in bone quality control.
“The observation that lacuno-canalicular remodeling is an essential component of bone mechanical competence sustains the view that osteocytes play an evolutionarily conserved role in bone quality control.98”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [98]
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- Authors
- Dole, N. S., Mazur, C. M., Acevedo, C., Lopez, J. P., Monteiro, D. A., Fowler, T. W., Gludovatz, B., Walsh, F., Regan, J. N., Messina, S., Evans, D. S., Lang, T. F., Zhang, B., Ritchie, R. O., Mohammad, K. S., & Alliston, T.
- Affiliations
- University of California, San Francisco (US)
- Lawrence Berkeley National Laboratory (US)
- Indiana University School of Medicine (US)
- California Pacific Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Alliston, Tamara
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 21
- Issue
- 9
- Pages
- 2585-2596
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6014615
- OpenAlex
- W2770060985
- Cited by
- 173
- References
- 52
- Citations by year
- 2026: 20 · 2025: 16 · 2024: 22 · 2023: 15 · 2022: 26 · 2021: 30 · 2020: 22 · 2019: 17 · 2018: 5
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
- Funders
- NIH-NIDCR (R01 DE019284)
- Department of Defense (DoD (PRORP OR130191)
- NSF (1636331, 1650113)
- NIH-NIAMS (R21 AR067439, P30 AR066262-01)
- Read Research Foundation
- OREF/ORS (17-008)
- NIH (T32 GM008155)
- DoD National Defense Science & Engineering graduate
- Swiss National Science Foundation (P300P2_167583)
- U.S. Department of Energy (DE-AC02-05CH11231)
- 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 › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Keywords
- osteocytes, TGF-beta signaling, bone quality, bone fragility, TGFBR2, bone homeostasis
- MeSH terms
- Animals, Bone and Bones, Cell Line, Immunohistochemistry, Male, Osteocytes, Signal Transduction, Transforming Growth Factor beta, Bone Remodeling, Mice
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