TY - JOUR
T1 - Senescent cells exacerbate chronic inflammation and contribute to periodontal disease progression in old mice
AU - Aquino-Martinez, Ruben
AU - Eckhardt, Brittany A.
AU - Rowsey, Jennifer L.
AU - Fraser, Daniel G.
AU - Khosla, Sundeep
AU - Farr, Joshua N.
AU - Monroe, David G.
N1 - Funding Information:
This work was supported by NIH grants R01 AG063707 (DGM), R01 AR068275 (DGM), R21 AG065868 (JNF), K01 AR070241 (JNF), P01 AG062413 (SK). We thank Paola Divieti Pajevic (Massachusetts General Hospital and Harvard Medical School, Boston, MN) for providing the Ocy454 cells. The authors report no conflicts of interest related to this study.
Funding Information:
This work was supported by NIH grants R01 AG063707 (DGM), R01 AR068275 (DGM), R21 AG065868 (JNF), K01 AR070241 (JNF), P01 AG062413 (SK). We thank Paola Divieti Pajevic (Massachusetts General Hospital and Harvard Medical School, Boston, MN) for providing the Ocy454 cells. The authors report no conflicts of interest related to this study.
Publisher Copyright:
© 2020 American Academy of Periodontology
PY - 2021/10
Y1 - 2021/10
N2 - Background: Coinciding with other chronic comorbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of age-related pathologies, where they promote “non-microbial” inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age. Methods: Alveolar bone samples were obtained from young (6 months) and old (20 to 22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte-enriched fractions were used to characterize the age-related senescence-associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS). Results: Increased senescence-associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin-6 (IL6), IL17, IGFBP4, and MMP13 were significantly upregulated with aging in osteocyte-enriched samples. Interestingly, SCM potentiated the LPS-induced expression of IL1α, IL1β, and IL6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190. Conclusions: Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell-intrinsic response to DNA damage, and a host-related mechanism associated with aging that could potentiate inflammation induced by bacterial components.
AB - Background: Coinciding with other chronic comorbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of age-related pathologies, where they promote “non-microbial” inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age. Methods: Alveolar bone samples were obtained from young (6 months) and old (20 to 22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte-enriched fractions were used to characterize the age-related senescence-associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS). Results: Increased senescence-associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin-6 (IL6), IL17, IGFBP4, and MMP13 were significantly upregulated with aging in osteocyte-enriched samples. Interestingly, SCM potentiated the LPS-induced expression of IL1α, IL1β, and IL6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190. Conclusions: Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell-intrinsic response to DNA damage, and a host-related mechanism associated with aging that could potentiate inflammation induced by bacterial components.
KW - DNA damage
KW - aging
KW - alveolar bone loss
KW - cellular senescence
KW - inflammation
KW - periodontal diseases
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U2 - 10.1002/JPER.20-0529
DO - 10.1002/JPER.20-0529
M3 - Article
C2 - 33341947
AN - SCOPUS:85099032294
SN - 0022-3492
VL - 92
SP - 1483
EP - 1495
JO - Journal of Periodontology
JF - Journal of Periodontology
IS - 10
ER -