Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

Changli Zhang, Madeline P. Smith, George K. Zhou, Alon Lai, Robert C. Hoy, Victoria Mroz, Olivia M. Torre, Damien M. Laudier, Elizabeth W. Bradley, Jennifer J. Westendorf, James C. Iatridis, Svenja Illien-Jünger

Research output: Contribution to journalArticle

Abstract

Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.

Original languageEnglish (US)
Article number754
JournalCell Death and Disease
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2019

Fingerprint

Intervertebral Disc Degeneration
Intervertebral Disc
Punctures
Needles
Apoptosis
Wounds and Injuries
Phosphoprotein Phosphatases
Back Pain
Caspase 3
Extracellular Matrix
Cell Survival
Collagen
Phosphorylation
Cell Proliferation
Research
Nucleus Pulposus
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice. / Zhang, Changli; Smith, Madeline P.; Zhou, George K.; Lai, Alon; Hoy, Robert C.; Mroz, Victoria; Torre, Olivia M.; Laudier, Damien M.; Bradley, Elizabeth W.; Westendorf, Jennifer J.; Iatridis, James C.; Illien-Jünger, Svenja.

In: Cell Death and Disease, Vol. 10, No. 10, 754, 01.10.2019.

Research output: Contribution to journalArticle

Zhang, Changli ; Smith, Madeline P. ; Zhou, George K. ; Lai, Alon ; Hoy, Robert C. ; Mroz, Victoria ; Torre, Olivia M. ; Laudier, Damien M. ; Bradley, Elizabeth W. ; Westendorf, Jennifer J. ; Iatridis, James C. ; Illien-Jünger, Svenja. / Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice. In: Cell Death and Disease. 2019 ; Vol. 10, No. 10.
@article{4accde118afc48ab96e9ac1d695e2b7b,
title = "Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice",
abstract = "Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.",
author = "Changli Zhang and Smith, {Madeline P.} and Zhou, {George K.} and Alon Lai and Hoy, {Robert C.} and Victoria Mroz and Torre, {Olivia M.} and Laudier, {Damien M.} and Bradley, {Elizabeth W.} and Westendorf, {Jennifer J.} and Iatridis, {James C.} and Svenja Illien-J{\"u}nger",
year = "2019",
month = "10",
day = "1",
doi = "10.1038/s41419-019-1985-3",
language = "English (US)",
volume = "10",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

AU - Zhang, Changli

AU - Smith, Madeline P.

AU - Zhou, George K.

AU - Lai, Alon

AU - Hoy, Robert C.

AU - Mroz, Victoria

AU - Torre, Olivia M.

AU - Laudier, Damien M.

AU - Bradley, Elizabeth W.

AU - Westendorf, Jennifer J.

AU - Iatridis, James C.

AU - Illien-Jünger, Svenja

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.

AB - Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.

UR - http://www.scopus.com/inward/record.url?scp=85072937812&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072937812&partnerID=8YFLogxK

U2 - 10.1038/s41419-019-1985-3

DO - 10.1038/s41419-019-1985-3

M3 - Article

C2 - 31582730

AN - SCOPUS:85072937812

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 10

M1 - 754

ER -