Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment

Ok Hee Jeon, Chaekyu Kim, Remi Martin Laberge, Marco Demaria, Sona Rathod, Alain P. Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J. Baker, Jan M. van Deursen, Judith Campisi, Jennifer Hartt Elisseeff

Research output: Contribution to journalArticle

Abstract

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

Original languageEnglish (US)
JournalNature Medicine
DOIs
StateAccepted/In press - Apr 24 2017

Fingerprint

Cartilage
Osteoarthritis
Ligaments
Pathology
Tissue
Renilla Luciferases
Knee prostheses
Anterior Cruciate Ligament
Articular Cartilage
Chondrocytes
Extracellular Matrix Proteins
Ports and harbors
Viruses
Surgery
Replacement Arthroplasties
Fusion reactions
Aging of materials
Pain
Intra-Articular Injections
Knee Replacement Arthroplasties

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. / Jeon, Ok Hee; Kim, Chaekyu; Laberge, Remi Martin; Demaria, Marco; Rathod, Sona; Vasserot, Alain P.; Chung, Jae Wook; Kim, Do Hun; Poon, Yan; David, Nathaniel; Baker, Darren J.; van Deursen, Jan M.; Campisi, Judith; Elisseeff, Jennifer Hartt.

In: Nature Medicine, 24.04.2017.

Research output: Contribution to journalArticle

Jeon, OH, Kim, C, Laberge, RM, Demaria, M, Rathod, S, Vasserot, AP, Chung, JW, Kim, DH, Poon, Y, David, N, Baker, DJ, van Deursen, JM, Campisi, J & Elisseeff, JH 2017, 'Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment', Nature Medicine. https://doi.org/10.1038/nm.4324
Jeon, Ok Hee ; Kim, Chaekyu ; Laberge, Remi Martin ; Demaria, Marco ; Rathod, Sona ; Vasserot, Alain P. ; Chung, Jae Wook ; Kim, Do Hun ; Poon, Yan ; David, Nathaniel ; Baker, Darren J. ; van Deursen, Jan M. ; Campisi, Judith ; Elisseeff, Jennifer Hartt. / Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. In: Nature Medicine. 2017.
@article{c44b5939983f4ece8a8012ba5445a83b,
title = "Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment",
abstract = "Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.",
author = "Jeon, {Ok Hee} and Chaekyu Kim and Laberge, {Remi Martin} and Marco Demaria and Sona Rathod and Vasserot, {Alain P.} and Chung, {Jae Wook} and Kim, {Do Hun} and Yan Poon and Nathaniel David and Baker, {Darren J.} and {van Deursen}, {Jan M.} and Judith Campisi and Elisseeff, {Jennifer Hartt}",
year = "2017",
month = "4",
day = "24",
doi = "10.1038/nm.4324",
language = "English (US)",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment

AU - Jeon, Ok Hee

AU - Kim, Chaekyu

AU - Laberge, Remi Martin

AU - Demaria, Marco

AU - Rathod, Sona

AU - Vasserot, Alain P.

AU - Chung, Jae Wook

AU - Kim, Do Hun

AU - Poon, Yan

AU - David, Nathaniel

AU - Baker, Darren J.

AU - van Deursen, Jan M.

AU - Campisi, Judith

AU - Elisseeff, Jennifer Hartt

PY - 2017/4/24

Y1 - 2017/4/24

N2 - Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

AB - Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

UR - http://www.scopus.com/inward/record.url?scp=85018396395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018396395&partnerID=8YFLogxK

U2 - 10.1038/nm.4324

DO - 10.1038/nm.4324

M3 - Article

C2 - 28436958

AN - SCOPUS:85018396395

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

ER -