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Cited by 91Bone fractures and treatmentsBone Metabolism and DiseasesAngiogenesis and VEGF in Cancer

TNFα contributes to diabetes impaired angiogenesis in fracture healing

Open access
Lim, Jason C., Ko, Kang I., Mattos, Marcelo, Fang, Miao, Zhang, Citong, Feinberg, Daniel, Sindi, Hisham, Li, Shuai +5 more·2017·Bone
DOI 10.1016/j.bone.2017.02.014PMC PMC5563392
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Abstract

Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.

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  • Aging leads to increased long-term expression of TNF-α, which delays early inflammation and cartilage formation in fracture healing and decreases overall VEGF, affecting angiogenesis and bone healing.

    “aging leads to increased long-term expression of TNF-α, which leads to delayed early inflammation and cartilage formation processes in fracture healing and a decrease in overall VEGF, which affects angiogenesis to the point of affecting bone healing”

    From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [90]

    The Introduction and Discussion (page numbers not supplied) link prolonged TNFα expression in diabetic fractures to reduced VEGFA expression and impaired angiogenesis. They do not establish aging as the cause, and they describe early inflammation as beneficial rather than delayed; the Introduction describes early cartilage resorption, not delayed cartilage formation. (LLM, conf=0.88)

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  1. [37]Kayal RA Siqueira M Alblowi J McLean J Krothapalli N Faibish D Einhorn TA Gerstenfeld LC Graves DT TNF-α mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1 Journal of Bone and Mineral Research 25 7 2010 1604 1615 20200974 PMC3154002

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Authors
Lim, J. C., Ko, K. I., Mattos, M., Fang, M., Zhang, C., Feinberg, D., Sindi, H., Li, S., Alblowi, J., Kayal, R. A., Einhorn, T. A., Gerstenfeld, L. C., & Graves, D. T.
Affiliations
  • University of Pennsylvania (US)
  • Shanxi Provincial People’s Hospital (CN)
  • Jilin University (CN)
  • Peking University (CN)
  • King Abdulaziz University (SA)
  • Boston University (US)
Corresponding author
Graves, Dana T.
ORCID
Venue
Bone
Publisher
Elsevier BV
Published
2017-06
Volume
99
Pages
26-38
ISSN
  • 1873-2763 (ISSN-L)
  • 8756-3282
DOI
10.1016/j.bone.2017.02.014
PMC
PMC5563392
OpenAlex
W2591689403
Cited by
91
References
36
Citations by year
2026: 16 · 2025: 7 · 2024: 6 · 2023: 7 · 2022: 10 · 2021: 12 · 2020: 15 · 2019: 8 · 2018: 6 · 2017: 4
FWCI
7.07
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Bone (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ScholarlyCommons (University of Pennsylvania) (submittedVersion, cc-by-nc-nd)
Funders
NIH (AR060055, DE019108)
Topics
  • Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
TNF-α, diabetes mellitus, fracture healing, angiogenesis, VEGF-A, chondrocytes, endothelial cell proliferation, endothelial cell apoptosis, FOXO1, advanced glycation end products, high glucose, inflammation, p21, caspase-3, endochondral ossification, microvascular endothelial cells, streptozotocin-induced diabetes
MeSH terms
Animals, Diabetes Mellitus, Experimental, Factor VIII, Hyperglycemia, Inflammation, Male, Polyethylene Glycols, Tumor Necrosis Factor-alpha, Fracture Healing, Antigens, CD34, Platelet Endothelial Cell Adhesion Molecule-1, Vascular Endothelial Growth Factor A, Receptors, Tumor Necrosis Factor, Type I, Mice

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