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Role Of Cellular Senescence in Age-Related Intervertebral Disc Degeneration

Patil, Prashanti (2019) Role Of Cellular Senescence in Age-Related Intervertebral Disc Degeneration. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Aging is one of the major risk factors for intervertebral disc degeneration (IDD). IDD is characterized by loss of disc matrix homeostasis due to decreased matrix synthesis and increased matrix breakdown. Elevated oxidative burden is closely associated with age-related IDD, and cellular senescence has been suggested as the mechanism by which oxidative stress perturbs the balance between disc anabolic and catabolic matrix homeostasis. Cellular senescence is characterized by a state of irreversible growth arrest and chronic secretion of increased inflammatory cytokines and matrix proteases. Increased number of senescent cells have been recorded with advancing age in discs of rodents and humans. In vitro studies have confirmed the catabolic nature of stress-induced senescent disc cells in promoting matrix homeostatic imbalance. However, the underlying molecular mechanism of senescent disc cells which enable their secretory phenotype and whether cellular senescence is causal in driving age-related IDD is yet to be ascertained. Herein, we examined the metabolic changes in oxidative stress-induced senescent (SIS) disc cells. Compared to non-senescent disc cells, SIS disc cells, in addition to acquiring a catabolic phenotype characterized by elevated fragmentation of aggrecan and collagen II and expression of IL-6 and IL-8, had upregulated mitochondrial content and ATP-linked respiration. This increase in mitochondrial ATP-linked respiration was driven by increased protein secretion in SIS disc cells because abrogation of protein synthesis using cycloheximide suppressed the mitochondrial ATP-linked respiration. As disc cells are known to rely on glycolysis, this result revealed heretofore unknown metabolic flexibility in disc cells to adapt to meet the underlying energy demand of their secretory phenotype. Next, we elucidated if a causal relationship existed between senescence and age-related IDD by examining the discs of p16-3MR transgenic mice following selective clearance of p16INK4a* senescent cells by the drug ganciclovir (GCV). In aged p16-3MR mice, treatment with GCV lowered the levels of disc MMP13, a major matrix protease, and reduced disc fragmentation of aggrecan. GCV-treated old mice also exhibited increased disc aggrecan and improved histological disc features. Altogether, these results suggest that cellular senescence adversely impacts the disc tissue and can serve as a therapeutic target to attenuate the age-related IDD.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Patil, Prashantiprp32@pitt.eduprp32
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMars, Wendy
Thesis AdvisorVo, Nam
Committee MemberPiganelli, Jon
Committee MemberSowa, Gwendolyn
Committee MemberDe Vallejo, Abbe
Committee MemberVan Houten, Bennett
Date: 14 January 2019
Date Type: Publication
Defense Date: 5 November 2018
Approval Date: 14 January 2019
Submission Date: 2 January 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 120
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: senescence; back pain; ageing; disc degeneration; senolytics;
Date Deposited: 14 Jan 2019 17:07
Last Modified: 14 Jan 2019 17:07
URI: http://d-scholarship.pitt.edu/id/eprint/35833

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