Kritschil, Rebecca
(2022)
Effects of autophagy inhibition on nucleus pulposus cell viability, function, and intervertebral disc degeneration.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Intervertebral disc degeneration (IDD) is a leading contributor to low back pain. The intervertebral disc (IVD) joint is composed of three tissue types: the central gelatinous nucleus pulposus (NP) tissue surrounded by the annulus fibrosus (AF) tissue and the inferior and superior cartilaginous endplates. The IVD microenvironment is hypoxic, acidic, hyperosmotic, and low in nutrients because it is mostly avascular. The cellular processes that underlie IDD initiation and progression are still poorly understood. Autophagy is a vital intracellular degradation process that removes damaged organelles, misfolded proteins, and intracellular pathogens and recycles the degraded components for cellular biosynthesis and energy production. Autophagy dysregulation is implicated in many age-related diseases, but the relationship between autophagy and IDD is not well characterized. Whether autophagy is vital for IVD cell health and function is a long-standing question in IVD biology. Here, I show evidence that short term autophagy inhibition in vitro is not essential for NP cell viability or function. I also generated a novel transgenic mouse strain (Col2a1-Cre; Atg7fl/fl) that disrupts autophagy specifically in NP tissue to determine whether autophagy inhibition leads to IDD in vivo. There were no differences in the level of apoptosis in Col2a1-Cre; Atg7fl/fl mice compared to control, in NP or AF tissue at 3, 6, or 12 months of age. Furthermore, NP-targeted autophagy inhibition did not affect proteoglycan content in NP of Col2a1-Cre; Atg7fl/fl mice compared to control at 12 months of age. H&E staining showed no significant IDD changes in Col2a1-Cre; Atg7fl/fl mice compared to control at 6 or 12 months of age. Collectively, the results do not support the current notion in the field that autophagy inhibition or dysregulation is a major contributor to IDD, at least in rodent models up to 12 months of age. More research is needed before therapeutic efforts to stimulate autophagy in NP cells is considered a valid endeavor. The data presented are the first to systematically study the essentiality of autophagy in normal, healthy NP cells both in vitro and in vivo.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
7 May 2022 |
| Date Type: |
Publication |
| Defense Date: |
13 December 2021 |
| Approval Date: |
7 May 2022 |
| Submission Date: |
9 January 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
147 |
| 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: |
autophagy, NP cells, intervertebral disc, intervertebral disc degeneration, low back pain, Atg7 |
| Date Deposited: |
07 May 2022 17:00 |
| Last Modified: |
07 May 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42165 |
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