Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Age-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice
Jiatong Liu, … , Hengwei Zhang, Lianping Xing
Jiatong Liu, … , Hengwei Zhang, Lianping Xing
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e148073. https://doi.org/10.1172/JCI148073.
View: Text | PDF
Research Article Aging Bone biology Article has an altmetric score of 8

Age-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice

  • Text
  • PDF
Abstract

Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF-β1. TGF-β–neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF-β1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF-β1 signaling is a molecular mechanism for fractures in the elderly via SCs.

Authors

Jiatong Liu, Jun Zhang, Xi Lin, Brendan F. Boyce, Hengwei Zhang, Lianping Xing

×

Figure 9

Senolytic drugs enhance fracture healing in female aged mice and reduce the expression of SASP factors in callus tissues.

Options: View larger image (or click on image) Download as PowerPoint
Senolytic drugs enhance fracture healing in female aged mice and reduce ...
Young and aged female mice underwent tibial fracture surgery. (A) Experimental outline. Mice were given 5 mg/kg dasatinib plus 50 mg/kg quercetin or vehicle by gavage on 3, 7, and 11 dpf and sacrificed on 14 dpf. n = 4–5. (B) The expression of p16 and p21 in callus tissues was determined by qPCR. Relative mRNA expression is the fold change versus vehicle-treated young mice as 1. (C) Callus volume was measured by micro-CT. (D) Representative images of ABH-stained sections showing more woven bone and callus areas in D+Q-treated aged mice than in vehicle-treated aged mice. Scale bar: 1 mm. (E) Woven bone and cartilage areas were analyzed using Visiopharm software. (F) The expression of SASP factors in callus tissues was measured by qPCR. Relative mRNA expression is the fold change versus vehicle-treated young mice as 1. (G) The concentration of active TGF-β1 protein in serum was measured by ELISA. *P < 0.05, for vehicle versus D+Q or vehicle young versus vehicle aged, by 2-way ANOVA followed by Tukey’s post hoc test (B, C, and E–G). (H) The expression of OB and OC marker genes in nonfractured bone and callus was determined by qPCR. Relative mRNA expression is the fold change versus bone samples from vehicle-treated young mice as 1. *P < 0.05 vehicle versus D+Q; #P < 0.05, for vehicle young bone versus vehicle aged bone, by 2-way ANOVA followed by Tukey’s post hoc test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 15 X users
On 1 Facebook pages
On 1 videos
45 readers on Mendeley
See more details