Cigarette Smoke Induces the Risk of Metabolic Bone Diseases: Transforming Growth Factor Beta Signaling Impairment via Dysfunctional Primary Cilia Affects Migration, Proliferation, and Differentiation of Human Mesenchymal Stem Cells
Open accessAbstract
It is well established that smoking has detrimental effects on bone integrity and is a preventable risk factor for metabolic bone disorders. Following orthopedic surgeries, smokers frequently show delayed fracture healing associated with many complications, which results in prolonged hospital stays. One crucial factor responsible for fracture repair is the recruitment and differentiation of mesenchymal stem cells (MSCs) at early stages, a mechanism mediated by transforming growth factor β (TGF-β). Although it is known that smokers frequently have decreased TGF-β levels, little is known about the actual signaling occurring in these patients. We investigated the effect of cigarette smoke on TGF-β signaling in MSCs to evaluate which step in the pathway is affected by cigarette smoke extract (CSE). Single-cell-derived human mesenchymal stem cell line (SCP-1 cells) were treated with CSE concentrations associated with smoking up to 20 cigarettes a day. TGF-β signaling was analyzed using an adenovirus-based reporter assay system. Primary cilia structure and downstream TGF-β signaling modulators (Smad2, Smad3, and Smad4) were analyzed by Western blot and immunofluorescence staining. CSE exposure significantly reduced TGF-β signaling. Intriguingly, we observed that protein levels of phospho-Smad2/3 (active forms) as well as nuclear translocation of the phospho-Smad3/4 complex decreased after CSE exposure, phenomena that affected signal propagation. CSE exposure reduced the activation of TGF-β modulators under constitutive activation of TGF-β receptor type I (ALK5), evidencing that CSE affects signaling downstream of the ALK5 receptor but not the binding of the cytokine to the receptor itself. CSE-mediated TGF-β signaling impaired MSC migration, proliferation, and differentiation and ultimately affected endochondral ossification. Thus, we conclude that CSE-mediated disruption of TGF-β signaling in MSCs is partially responsible for delayed fracture healing in smokers.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cigarette smoke contains compounds that may affect osteogenic and chondrogenic differentiation.
“Aspera-Werz reported that cigarette smoke contains compounds that may affect osteogenic and chondrogenic differentiation [61].”
From Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic (2021) · cites this paper as [61]
A decrease in serum levels of transforming growth factor-beta occurs in smokers, impairing the recruitment, proliferation, and differentiation of mesenchymal stem cells into fibroblasts, osteoblasts, and chondrocytes, and negatively affecting soft callus and hard callus formation.
“Indeed, it has been observed that a decrease in serum levels of transforming growth factor-beta (TGF-β) occurs in smokers, impairing the recruitment, proliferation, and differentiation of mesenchymal stem cells (MSCs) in fibroblasts, osteoblasts, and chondrocytes. This effect, in turn, negatively affects the soft callus and hard callus formation phase [61].”
From Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic (2021) · cites this paper as [61]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 75 · Cited by 58
Research works printed but not linked: 14
- Burns, D.M. Tobacco-related diseases. Semin. Oncol. Nurs. 2003, 19, 244-249.
- Kanis, J.A.; Johnell, O.; Oden, A.; Johansson, H.; De Laet, C.; Eisman, J.A.; Fujiwara, S.; Kroger, H.; McCloskey, E.V.; Mellstrom, D.; et al. Smoking and fracture risk: A meta-analysis. Osteoporos. Int. 2005, 16, 155-162.
- Yoon, V.; Maalouf, N.M.; Sakhaee, K. The effects of smoking on bone metabolism. Osteoporos. Int. 2012, 23, 2081-2092.
- Ko, C.H.; Chan, R.L.; Siu, W.S.; Shum, W.T.; Leung, P.C.; Zhang, L.; Cho, C.H. Deteriorating effect on bone metabolism and microstructure by passive cigarette smoking through dual actions on osteoblast and osteoclast. Calcif. Tissue Int. 2015, 96, 389-400.
- Mäkitie, R.E.; Costantini, A.; Kämpe, A.; Alm, J.J.; Mäkitie, O. New insights into monogenic causes of osteoporosis. Front. Endocrinol. 2019, 10, 70.
- Feng, X.; McDonald, J.M. Disorders of bone remodeling. Annu. Rev. Pathol. 2011, 6, 121-145.
- Zhang, Y.E. Non-smad pathways in tgf-β signaling. Cell Res. 2008, 19, 128.
- Li, R.D.; Deng, Z.L.; Hu, N.; Liang, X.; Liu, B.; Luo, J.; Chen, L.; Yin, L.; Luo, X.; Shui, W.; et al. Biphasic effects of tgfbeta1 on bmp9-induced osteogenic differentiation of mesenchymal stem cells. BMB Rep. 2012, 45, 509-514.
- Ward, K.D.; Klesges, R.C. A meta-analysis of the effects of cigarette smoking on bone mineral density. Calcif. Tissue Int. 2001, 68, 259-270. [CrossRef] [PubMed] · DOI · Paper page
- Even Dar, R.; Mazor, Y.; Karban, A.; Ish-Shalom, S.; Segal, E. Risk factors for low bone density in inflammatory bowel disease: Use of glucocorticoids, low body mass index, and smoking. Dig. Dis. 2019, 37, 284-290. [CrossRef] · DOI
- Greenblatt, M.B.; Tsai, J.N.; Wein, M.N. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin. Chem. 2017, 63, 464-474. [CrossRef] · DOI · Paper page
- Centrella, M.; McCarthy, T.L.; Canalis, E. Skeletal tissue and transforming growth factor beta. FASEB J. 1988, 2, 3066-3073. [CrossRef] [PubMed] · DOI
- Poniatowski, L.A.; Wojdasiewicz, P.; Gasik, R.; Szukiewicz, D. Transforming growth factor beta family: Insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. Med. Inflam. 2015, 2015, 137823. [CrossRef] [PubMed] · DOI
- Zimmermann, G.; Henle, P.; Kusswetter, M.; Moghaddam, A.; Wentzensen, A.; Richter, W.; Weiss, S. Tgf-beta1 as a marker of delayed fracture healing. Bone 2005, 36, 779-785. [CrossRef] [PubMed] · DOI
- Authors
- Aspera-Werz, R. H., Chen, T., Ehnert, S., Zhu, S., Fröhlich, T., & Nussler, A. K.
- Affiliations
- University of Tübingen (DE)
- Corresponding author
- Aspera-Werz, Romina H.
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2019-06-14
- Volume
- 20
- Issue
- 12
- Pages
- 2915
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC6628373
- OpenAlex
- W2950378633
- Cited by
- 58
- References
- 75
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 3 · 2022: 9 · 2021: 16 · 2020: 9 · 2019: 2
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Eberhard Karls Universität Tübingen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- cigarette smoke extract, smoking, metabolic bone disease, mesenchymal stem cells, TGF-beta signaling, primary cilia, ALK5, endochondral ossification, fracture healing, stem cell migration, stem cell proliferation, stem cell differentiation
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Bone Diseases, Metabolic, Cell Differentiation, Cell Line, Cell Movement, Cilia, Humans, Tobacco Smoke Pollution, Signal Transduction, Transforming Growth Factor beta, Cell Proliferation, Smad Proteins, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
