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

Autor: Victoria Mroz, Changli Zhang, Elizabeth W. Bradley, George Zhou, Olivia M. Torre, Alon Lai, Svenja Illien-Jünger, Robert C Hoy, James C. Iatridis, Madeline P. Smith, Jennifer J. Westendorf, Damien M. Laudier
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
Cancer Research
Apoptosis
Intervertebral Disc Degeneration
Matrix (biology)
Extracellular matrix
0302 clinical medicine
Phosphoprotein Phosphatases
Medicine
Aggrecans
Phosphorylation
Child
Aged
80 and over
0303 health sciences
Caspase 3
lcsh:Cytology
Immunochemistry
Nuclear Proteins
Middle Aged
musculoskeletal system
medicine.anatomical_structure
Needles
Female
Collagen
musculoskeletal diseases
Nucleus Pulposus
Phosphorylases
Immunology
Punctures
Article
03 medical and health sciences
Cellular and Molecular Neuroscience
Animals
Humans
lcsh:QH573-671
Protein kinase B
Aged
Cell Proliferation
030304 developmental biology
Cell growth
Akt/PKB signaling pathway
business.industry
Intervertebral disc
Cell Biology
Spine
Mice
Inbred C57BL
Cancer research
business
Proto-Oncogene Proteins c-akt
030217 neurology & neurosurgery
Zdroj: Cell Death and Disease, Vol 10, Iss 10, Pp 1-15 (2019)
Cell Death & Disease
ISSN: 2041-4889
DOI: 10.1038/s41419-019-1985-3
Popis: 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.
Databáze: OpenAIRE
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