TGF-β Induces Wnt10b in Osteoclasts From Female Mice to Enhance Coupling to Osteoblasts
Open accessAbstract
In young adults, bone lost through osteoclast-mediated resorption is precisely replaced in both location and amount. Understanding how these two processes are coupled is crucial to advancing treatments for osteoporosis, a disease that progresses when the processes become uncoupled. We documented that osteoclasts secrete the mammalian integration 1 gene that is the homolog of Drosophila Wngless (Wnt) 10b, bone morphogenetic protein 6 (BMP6), and the chemokine sphingosin 1 phosphate (S1P) to promote mesenchymal cell mineralization in vitro. During bone resorption, TGF-β1 is released from the bone extracellular matrix and activated by osteoclasts. Thus, TGF-β1 levels are elevated during the resorption phase of bone turnover. We therefore investigated the influences of TGF-β1 on osteoclast-mediated support of mineralization. TGF-β1 increased osteoclast production of Wnt10b, but not BMP6 or S1P. Blocking Wnt10b activity with the Wnt signaling inhibitor Dickkoph-related protein 1 suppressed the ability of TGF-β–treated osteoclast-conditioned media to promote osteoblast mineralization. Examination of TGF-β signaling in osteoclasts revealed that induction of Wnt10b expression was dependent on Smad2/3 activation and independent from TGF-β1 stimulation of protein kinase B (AKT) or MAPK kinase. TGF-β1–treated osteoclast-conditioned media from cells with blocked Smad signaling exhibited a reduced ability to support mineralization, demonstrating the importance of Smad signaling in this response. Parallel cultures with suppressed TGF-β activation of AKT or MAPK kinase signaling retained their ability to elevate mineralization. These results demonstrate that TGF-β1 stimulates Wnt10b production in osteoclasts, which may enhance restoration of the bone lost during the resorptive phase of bone turnover.
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TGF-β1 has a dual effect on osteoblasts by directly recruiting their progenitors to the bone surface and indirectly promoting matrix mineralization through osteoclast-derived Wnt10b.
“TGF-β1 therefore has a dual effect on osteoblasts by directly recruiting their progenitors to the bone surface and by indirectly promoting matrix mineralization through osteoclast-derived Wnt10b.211”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [211]
TGF-β1 release enhances Wnt10b expression and secretion to stimulate osteoblast-directed mineralization.
“Indeed, TGF-β1 release enhances Wnt10b expression and secretion to stimulate osteoblast-directed mineralization.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [211]
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Bone remodeling: an operational process ensuring survival and bone mechanical competence
Bolamperti, S., Villa, I., & Rubinacci, A. (2022) · Bone Research · doi:10.1038/s41413-022-00219-8 · Cited by 482 · see citing works
- Authors
- Ota, K., Quint, P., Ruan, M., Pederson, L., Westendorf, J. J., Khosla, S., & Oursler, M. J.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Oursler, Merry Jo
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2013-10-01
- Volume
- 154
- Issue
- 10
- Pages
- 3745-3752
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3776874
- OpenAlex
- W2036508612
- Cited by
- 86
- References
- 34
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 12 · 2021: 10 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 7 · 2016: 9 · 2015: 9 · 2014: 4 · 2013: 1
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Foundation for Medical Education and Research
- National Institutes of Health (DK07352, AG004875)
- National Institute on Aging (P01AG004875)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-07352, T32DK007352)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TGF-β1, Wnt10b, osteoclasts, osteoblast mineralization, bone remodeling, bone resorption, Smad2/3 signaling, Dickkopf-related protein 1, BMP6, sphingosine-1-phosphate, osteoporosis, bone turnover
- MeSH terms
- Animals, Animals, Newborn, Calcification, Physiologic, Cell Communication, Cells, Cultured, Female, Gene Expression Regulation, Lysophospholipids, Mice, Inbred C57BL, Osteoblasts, Osteoclasts, RNA, Messenger, Sphingosine, Signal Transduction, Culture Media, Conditioned, Intercellular Signaling Peptides and Proteins, Wnt Proteins, Mice, Smad Proteins, Receptor-Regulated, Transforming Growth Factor beta1, Bone Morphogenetic Protein 6
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