Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ
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The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.
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In mice, FGF21 has been reported to promote bone loss, but this effect has not been independently validated in rodents or obese non-human primates.
“In mice, FGF21 has been reported to promote bone loss96,97, but this effect has not been independently validated in rodents98 or obese non-human primates99.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [96]
In mice, FGF21 has been reported to promote bone loss, but this finding could not be replicated.
“In mice, FGF21 has been reported to promote bone loss (134, 135); however, this finding could not be replicated (80).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [135]
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FGF21 Is Not a Major Mediator for Bone Homeostasis or Metabolic Actions of PPARα and PPARγ Agonists
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Fgf21 Impairs Adipocyte Insulin Sensitivity in Mice Fed a Low-Carbohydrate, High-Fat Ketogenic Diet
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Bone-muscle crosstalk under physiological and pathological conditions
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Age-related bone loss is associated with FGF21 but not IGFBP1 in healthy adults
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An updated patent review of GLP-1 receptor agonists (2020-present)
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- Authors
- Wei, W., Dutchak, P. A., Wang, X., Ding, X., Wang, X., Bookout, A. L., Goetz, R., Mohammadi, M., Gerard, R. D., Dechow, P. C., Mangelsdorf, D. J., Kliewer, S. A., & Wan, Y.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- New York University (US)
- Molecular Biology,
- Department of Biomedical Sciences, Baylor College of Dentistry, Texas A & M University Health Sciences Center, Dallas, TX 75246
- Howard Hughes Medical Institute (US)
- Departments of aPharmacology and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-02-06
- Volume
- 109
- Issue
- 8
- Pages
- 3143-3148
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3286969
- OpenAlex
- W2043531340
- Cited by
- 426
- References
- 47
- Citations by year
- 2026: 25 · 2025: 28 · 2024: 36 · 2023: 20 · 2022: 21 · 2021: 24 · 2020: 26 · 2019: 27 · 2018: 34 · 2017: 30 · 2016: 36 · 2015: 37 · 2014: 30 · 2013: 30 · 2012: 22
- FWCI
- 15.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute (I-1558, I-1275)
- March of Dimes Foundation
- Cancer Prevention and Research Institute of Texas (RP100841)
- National Institutes of Health (I-1275, I-1558)
- National Institute of General Medical Sciences (T32GM007062, GM007062, RL1GM084436)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK089113, U19DK062434, R56DK089600)
- National Institute of Dental and Craniofacial Research (DE13686, R01DE013686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- 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
- Keywords
- FGF21, PPARγ, bone loss, skeletal homeostasis, osteoblastogenesis, adipogenesis, bone marrow mesenchymal stem cells, rosiglitazone, type 2 diabetes, bone fragility, energy metabolism
- MeSH terms
- Rosiglitazone, Animals, Bone and Bones, Bone Marrow, Bone Resorption, Drug Resistance, Fibroblast Growth Factors, Humans, Organ Size, Osteoblasts, Osteogenesis, Mice, Knockout, Thiazolidinediones, PPAR gamma, Adipogenesis, Mice, Osteoprotegerin, RANK Ligand
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.
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