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 H. Elisseeff

doi:10.1038/nm.4324

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 H. Elisseeff

Research output: Contribution to journal › Article › peer-review

860 Citations (Scopus)

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 p16 INK4a (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 language	English
Pages (from-to)	775-781
Number of pages	7
Journal	Nature Medicine
Volume	23
Issue number	6
DOIs	https://doi.org/10.1038/nm.4324
Publication status	Published - 2017 Jun 1
Externally published	Yes

Bibliographical note

Funding Information:
We thank J. Xu (F.M. Kirby Research Center at Johns Hopkins University) for in vivo luminescence imaging, A. Bendele (Bolder Biopath, Inc.) for the subchondral bone damage analysis and Y. Oh (Johns Hopkins University) for immunoblotting. This work was supported by Unity Biotechnology, Inc. (J.H.E., A.P.V., Y.P., N.D.), the Bloomberg-Kimmel Institute for Cancer Immunotherapy (J.H.E.), the Morton Goldberg Professorship (J.H.E.), National Institute on Aging (NIA) grant AG017242 (J.C.), AG009909 (M.D.), National Cancer Institute (NCI) grant R01CA96985 (J.M.v.D.), a grant from the Paul F. Glenn Foundation (J.M.v.D. and D.J.B.) and a Fulbright scholarship from the Institute of International Education (O.H.J.).

Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm.4324

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Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., Chung, J. W., Kim, D. H., Poon, Y., David, N., Baker, D. J., Van Deursen, J. M., Campisi, J., & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature Medicine, 23(6), 775-781. https://doi.org/10.1038/nm.4324

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, vol. 23, no. 6, pp. 775-781. https://doi.org/10.1038/nm.4324

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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 p16 INK4a (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 H.}",

note = "Funding Information: We thank J. Xu (F.M. Kirby Research Center at Johns Hopkins University) for in vivo luminescence imaging, A. Bendele (Bolder Biopath, Inc.) for the subchondral bone damage analysis and Y. Oh (Johns Hopkins University) for immunoblotting. This work was supported by Unity Biotechnology, Inc. (J.H.E., A.P.V., Y.P., N.D.), the Bloomberg-Kimmel Institute for Cancer Immunotherapy (J.H.E.), the Morton Goldberg Professorship (J.H.E.), National Institute on Aging (NIA) grant AG017242 (J.C.), AG009909 (M.D.), National Cancer Institute (NCI) grant R01CA96985 (J.M.v.D.), a grant from the Paul F. Glenn Foundation (J.M.v.D. and D.J.B.) and a Fulbright scholarship from the Institute of International Education (O.H.J.). Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature. All rights reserved.",

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doi = "10.1038/nm.4324",

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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 H.

N1 - Funding Information: We thank J. Xu (F.M. Kirby Research Center at Johns Hopkins University) for in vivo luminescence imaging, A. Bendele (Bolder Biopath, Inc.) for the subchondral bone damage analysis and Y. Oh (Johns Hopkins University) for immunoblotting. This work was supported by Unity Biotechnology, Inc. (J.H.E., A.P.V., Y.P., N.D.), the Bloomberg-Kimmel Institute for Cancer Immunotherapy (J.H.E.), the Morton Goldberg Professorship (J.H.E.), National Institute on Aging (NIA) grant AG017242 (J.C.), AG009909 (M.D.), National Cancer Institute (NCI) grant R01CA96985 (J.M.v.D.), a grant from the Paul F. Glenn Foundation (J.M.v.D. and D.J.B.) and a Fulbright scholarship from the Institute of International Education (O.H.J.). Publisher Copyright: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

PY - 2017/6/1

Y1 - 2017/6/1

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 p16 INK4a (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 p16 INK4a (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.

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

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