Abstract
Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1−/Δ mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence-associated β-galactosidase activity, γH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 16-23 |
| Number of pages | 8 |
| Journal | Mechanisms of Ageing and Development |
| Volume | 166 |
| DOIs | |
| State | Published - Sep 2017 |
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Keywords
- Aging
- Cellular senescence
- DNA damage
- Intervertebral disc
- Matrix proteoglycan
Cite this
Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype. / Ngo, Kevin; Patil, Prashanti; McGowan, Sara J.; Niedernhofer, Laura J.; Robbins, Paul D.; Kang, James; Sowa, Gwendolyn; Vo, Nam.
In: Mechanisms of Ageing and Development, Vol. 166, 09.2017, p. 16-23.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype
AU - Ngo, Kevin
AU - Patil, Prashanti
AU - McGowan, Sara J.
AU - Niedernhofer, Laura J.
AU - Robbins, Paul D.
AU - Kang, James
AU - Sowa, Gwendolyn
AU - Vo, Nam
PY - 2017/9
Y1 - 2017/9
N2 - Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1−/Δ mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence-associated β-galactosidase activity, γH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss.
AB - Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1−/Δ mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence-associated β-galactosidase activity, γH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss.
KW - Aging
KW - Cellular senescence
KW - DNA damage
KW - Intervertebral disc
KW - Matrix proteoglycan
UR - http://www.scopus.com/inward/record.url?scp=85028425897&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028425897&partnerID=8YFLogxK
U2 - 10.1016/j.mad.2017.08.007
DO - 10.1016/j.mad.2017.08.007
M3 - Article
C2 - 28830687
AN - SCOPUS:85028425897
VL - 166
SP - 16
EP - 23
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
SN - 0047-6374
ER -