Transforming Growth Factor-β-induced Osteoblast Elongation Regulates Osteoclastic Bone Resorption through a p38 Mitogen-activated Protein Kinase- and Matrix Metalloproteinase-dependent Pathway
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Transforming growth factor-beta (TGF-beta) is a powerful modulator of bone metabolism, and both its anabolic and catabolic effects on bone have been described. Here we have tested the hypothesis that TGF-beta-induced changes in osteoblast shape promote bone resorption by increasing the surface area of bone that is accessible to osteoclasts. The addition of TGF-beta1 to MC3T3-E1 cells resulted in cytoskeletal reorganization, augmented expression of focal adhesion kinase, and cell elongation, accompanied by an increase in the area of cell-free substratum. TGF-beta1 also triggered activation of Erk1/2 and p38 mitogen-activated protein (MAP) kinase. The p38 MAP kinase inhibitor PD169316, but not an inhibitor of the Erk1/2 pathway, abrogated the effect of TGF-beta1 on cell shape. The matrix metalloproteinase inhibitor GM6001 also interfered with osteoblast elongation. Treatment of MC3T3-E1 cells seeded at confluence onto bone slices to mimic a bone lining cell layer with TGF-beta1 also induced cell elongation and increased pit formation by subsequently added osteoclasts. These effects were again blocked by PD169316 and GM6001. We propose that this novel pathway regulating osteoblast morphology plays an important role in the catabolic effects of TGF-beta on bone metabolism.
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TGF-β1 is important for inducing cytoskeletal reorganization via the p38 pathway in osteoblastic cells, which elongate to generate cell-free areas.
“TGF-β1 is important for inducing cytoskeletal reorganization via the p38 pathway in osteoblastic cells, which elongate to generate cell-free areas.141”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [141]
MMP inhibitors prevent osteoblast elongation and generation of cell-free areas and directly act on osteoclasts by preventing their migration through the cell layer.
“Metalloproteinase (MMP) inhibitors prevent both osteoblast elongation and the subsequent generation of cell-free areas143 and directly act on osteoclasts by preventing their migration through the cell layer.141”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [141]
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- Authors
- Karsdal, M. A., Fjording, M. S., Foged, N. T., Delaissé, J.-M., & Lochter, A.
- Affiliations
- Center for Clinical & Basic Research (DK)
- Leo Pharma (Denmark) (DK)
- Corresponding author
- Karsdal, Morten A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 276
- Issue
- 42
- Pages
- 39350-39358
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1971000202
- Cited by
- 81
- References
- 74
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 1 · 2015: 1 · 2014: 5 · 2013: 3 · 2012: 1
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- TGF-β1, osteoclast resorption, p38 MAPK, matrix metalloproteinases, ERK signaling, focal adhesion kinase, cytoskeletal remodeling, osteoblast morphology, bone lining cells, pit formation, PD169316, GM6001
- MeSH terms
- Animals, Bone Resorption, Cell Division, Cell-Free System, Cells, Cultured, Dipeptides, Dose-Response Relationship, Drug, Enzyme Inhibitors, Imidazoles, Osteoblasts, Osteoclasts, Protein Binding, Protein-Tyrosine Kinases, Time Factors, Blotting, Western, Signal Transduction, Transforming Growth Factor beta, 3T3 Cells, Culture Media, Serum-Free, Fluorescent Antibody Technique, Indirect, Mitogen-Activated Protein Kinase 1, Matrix Metalloproteinases, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Mice, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesion Kinase 1
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