Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis

E. W. Bradley, L. R. Carpio, Meghan Elizabeth McGee Lawrence, C. Castillejo Becerra, D. F. Amanatullah, L. E. Ta, M. Otero, M. B. Goldring, S. Kakar, J. J. Westendorf

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Objective: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. Design: Knee joints of WT and Phlpp1-/- mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. Results: Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1-/- mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. Conclusion: Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.

Original languageEnglish (US)
Pages (from-to)1021-1028
Number of pages8
JournalOsteoarthritis and Cartilage
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2016

Fingerprint

Cartilage
Osteoarthritis
Methylation
Inflammation
Chondrocytes
Surgery
Articular Cartilage
Cells
Joints
Ligaments
Phosphatases
Cell Line
Femoral Neck Fractures
Deterioration
Phosphoprotein Phosphatases
Assays
Cytosine
Hyperalgesia
Bone
Repair

Keywords

  • Articular cartilage
  • DMM mouse model
  • DNA methylation
  • Il6
  • Mechanical allodynia
  • TNFα

ASJC Scopus subject areas

  • Rheumatology
  • Biomedical Engineering
  • Orthopedics and Sports Medicine

Cite this

Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. / Bradley, E. W.; Carpio, L. R.; McGee Lawrence, Meghan Elizabeth; Castillejo Becerra, C.; Amanatullah, D. F.; Ta, L. E.; Otero, M.; Goldring, M. B.; Kakar, S.; Westendorf, J. J.

In: Osteoarthritis and Cartilage, Vol. 24, No. 6, 01.06.2016, p. 1021-1028.

Research output: Contribution to journalArticle

Bradley, EW, Carpio, LR, McGee Lawrence, ME, Castillejo Becerra, C, Amanatullah, DF, Ta, LE, Otero, M, Goldring, MB, Kakar, S & Westendorf, JJ 2016, 'Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis', Osteoarthritis and Cartilage, vol. 24, no. 6, pp. 1021-1028. https://doi.org/10.1016/j.joca.2015.12.014
Bradley, E. W. ; Carpio, L. R. ; McGee Lawrence, Meghan Elizabeth ; Castillejo Becerra, C. ; Amanatullah, D. F. ; Ta, L. E. ; Otero, M. ; Goldring, M. B. ; Kakar, S. ; Westendorf, J. J. / Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. In: Osteoarthritis and Cartilage. 2016 ; Vol. 24, No. 6. pp. 1021-1028.
@article{58438a2a67294376a17d17bb23456cd6,
title = "Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis",
abstract = "Objective: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. Design: Knee joints of WT and Phlpp1-/- mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. Results: Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1-/- mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. Conclusion: Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.",
keywords = "Articular cartilage, DMM mouse model, DNA methylation, Il6, Mechanical allodynia, TNFα",
author = "Bradley, {E. W.} and Carpio, {L. R.} and {McGee Lawrence}, {Meghan Elizabeth} and {Castillejo Becerra}, C. and Amanatullah, {D. F.} and Ta, {L. E.} and M. Otero and Goldring, {M. B.} and S. Kakar and Westendorf, {J. J.}",
year = "2016",
month = "6",
day = "1",
doi = "10.1016/j.joca.2015.12.014",
language = "English (US)",
volume = "24",
pages = "1021--1028",
journal = "Osteoarthritis and Cartilage",
issn = "1063-4584",
publisher = "W.B. Saunders Ltd",
number = "6",

}

TY - JOUR

T1 - Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis

AU - Bradley, E. W.

AU - Carpio, L. R.

AU - McGee Lawrence, Meghan Elizabeth

AU - Castillejo Becerra, C.

AU - Amanatullah, D. F.

AU - Ta, L. E.

AU - Otero, M.

AU - Goldring, M. B.

AU - Kakar, S.

AU - Westendorf, J. J.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Objective: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. Design: Knee joints of WT and Phlpp1-/- mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. Results: Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1-/- mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. Conclusion: Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.

AB - Objective: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. Design: Knee joints of WT and Phlpp1-/- mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. Results: Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1-/- mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. Conclusion: Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.

KW - Articular cartilage

KW - DMM mouse model

KW - DNA methylation

KW - Il6

KW - Mechanical allodynia

KW - TNFα

UR - http://www.scopus.com/inward/record.url?scp=84955277705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955277705&partnerID=8YFLogxK

U2 - 10.1016/j.joca.2015.12.014

DO - 10.1016/j.joca.2015.12.014

M3 - Article

C2 - 26746148

AN - SCOPUS:84955277705

VL - 24

SP - 1021

EP - 1028

JO - Osteoarthritis and Cartilage

JF - Osteoarthritis and Cartilage

SN - 1063-4584

IS - 6

ER -