Roles of stromal cell RANKL, OPG, and M‐CSF expression in biphasic TGF‐β regulation of osteoclast differentiation
Open accessAbstract
To better understand the complex roles of transforming growth factor‐beta (TGF‐β) in bone metabolism, we examined the impact of a range of TGF‐β concentrations on osteoclast differentiation. In co‐cultures of support cells and spleen or marrow osteoclast precursors, low TGF‐β concentrations stimulated while high concentrations inhibited differentiation. We investigated the influences of TGF‐β on macrophage colony stimulating factor (M‐CSF), receptor activator of NF‐κB ligand (RANKL), and osteoprotegerin (OPG) expression and found a dose dependent inhibition of M‐CSF expression. RANKL expression was elevated at low TGF‐β concentrations with a less dramatic increase in OPG. Addition of OPG blocked differentiation at the stimulatory TGF‐β dose. Thus, low TGF‐β concentrations elevated the RANKL/OPG ratio while high concentrations did not, supporting that, at low TGF‐β concentrations, there is sufficient M‐CSF and a high RANKL/OPG ratio to stimulate differentiation. At high TGF‐β concentrations, the RANKL/OPG ratio and M‐CSF expression were both repressed and there was no differentiation. We examined whether TGF‐β‐mediated repression of osteoclasts differentiation is due to these changes by adding M‐CSF and/or RANKL and did not observe any impact on differentiation repression. We studied direct TGF‐β impacts on osteoclast precursors by culturing spleen or marrow cells with M‐CSF and RANKL. TGF‐β treatment dose‐dependently stimulated osteoclast differentiation. These data indicate that low TGF‐β levels stimulate osteoclast differentiation by impacting the RANKL/OPG ratio while high TGF‐β levels repress osteoclast differentiation by multiple avenues including mechanisms independent of the RANKL/OPG ratio or M‐CSF expression regulation. © 2004 Wiley‐Liss, Inc.
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Different concentrations of TGF-β have different effects on the RANKL/OPG ratio and osteoclast differentiation: low concentrations increase stimulation of osteoclast differentiation, while high concentrations have the opposite effect.
“Different concentrations of TGF-β have different effects on the RANKL/OPG ratio and ultimately on osteoclast differentiation (low concentrations of TGF-β increase the stimulation of osteoclast differentiation, while high concentrations of TGF-β have the opposite effect) [98, 99].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [98]
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- Authors
- Karst, M., Gorny, G., Galvin, R. J. S., & Oursler, M. J.
- Affiliations
- University of Minnesota, Duluth (US)
- Eli Lilly (United States) (US)
- Mayo Clinic (US)
- Corresponding author
- Oursler, Merry Jo
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2004-02-17
- Volume
- 200
- Issue
- 1
- Pages
- 99-106
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- PMC
- PMC4547836
- OpenAlex
- W2071619258
- Cited by
- 184
- References
- 34
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 10 · 2023: 9 · 2022: 10 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 20 · 2017: 4 · 2016: 8 · 2015: 4 · 2014: 6 · 2013: 11 · 2012: 4
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Dental and Craniofacial Research (DE 14680, R01DE014680)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- TGF-beta, osteoclastogenesis, RANKL, osteoprotegerin, macrophage colony-stimulating factor, RANKL/OPG ratio, bone metabolism, dose-dependent regulation, osteoclast precursors, stromal cells, bone remodeling
- MeSH terms
- Animals, Bone Marrow Cells, Carrier Proteins, Cell Differentiation, Cells, Cultured, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Glycoproteins, Membrane Glycoproteins, Mice, Inbred BALB C, Osteoclasts, Spleen, Macrophage Colony-Stimulating Factor, Transforming Growth Factor beta, Stromal Cells, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Coculture Techniques, Mice, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Transforming Growth Factor beta1, Transforming Growth Factor beta2
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