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.
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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

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

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Figure 1

Increase in p16+ SCs in fracture callus of aged mice.

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Increase in p16+ SCs in fracture callus of aged mice. Young and aged mic...
Young and aged mice underwent tibial fracture surgery and were sacrificed at 10 dpf. (A) Expression of p16 and p21 in callus tissue was measured by qPCR at the indicated time points. n = 3. Relative mRNA expression is the fold change versus young samples at time 0 as 1. *P < 0.05 aged versus young; #P < 0.05 young versus young 0 dpf; and ^P < 0.05 aged versus aged 0 dpf, by 2-way ANOVA followed by Tukey’s post hoc test. (B and C) Frozen sections of callus were immunostained with anti-p16 Ab or SA–β-gal. External callus is indicated by a dashed line and cartilage by a solid line. WB, woven bone. (B) Representative images showing increased p16+ cells in the aged sample. Scale bar: 1 mm. The number and percentage of p16+ cells were quantified by ImageJ. n = 4. (C) Representative images showing increased SA–β-gal+ cells in the aged sample. Scale bar: 1 mm. Original magnification, ×7 (enlarged insets in B) and ×3.5 (enlarged insets in C). SA–β-gal+ cells were quantified by ImageJ. n = 3. *P < 0.05, by unpaired, 2-tailed Student’s t test.