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

Nature Medicine volume 23, pages 775–781 (2017)Cite this article

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Abstract

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies1,2,3, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP)4,5,6. Removal of SnCs delays several pathologies7,8,9 and increases healthy lifespan8. Aging and trauma are risk factors for the development of osteoarthritis (OA)10, 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 surgery11,12,13,14, 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)15,16. 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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Figure 1: Clearance of SnCs by GCV reduces the development of post-traumatic OA.
Figure 2: SnC clearance by UBX0101 attenuates post-traumatic OA and creates a prochondrogenic environment.
Figure 3: Clearance of SnCs slows the development of naturally occurring OA and post-traumatic OA in aged mice.
Figure 4: UBX0101 clears SnCs by inducing apoptosis and improves the cartilage-forming ability of chondrocytes from human OA tissue.

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Acknowledgements

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.).

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Author notes

  1. Ok Hee Jeon and Chaekyu Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, Maryland, USA

    Ok Hee Jeon, Chaekyu Kim, Sona Rathod, Jae Wook Chung, Do Hun Kim & Jennifer H Elisseeff

  2. Department of Chemistry, Ulsan National Institute of Science and Technology, Ulsan, South Korea

    Chaekyu Kim

  3. Buck Institute for Research on Aging, Novato, California, USA

    Remi-Martin Laberge, Marco Demaria & Judith Campisi

  4. Unity Biotechnology, Inc., Brisbane, California, USA

    Remi-Martin Laberge, Alain P Vasserot, Yan Poon & Nathaniel David

  5. European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Marco Demaria

  6. Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Darren J Baker & Jan M van Deursen

  7. Lawrence Berkeley National Laboratory, University of California, Berkeley, Berkley, California, USA.,

    Judith Campisi

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Contributions

O.H.J. and C.K. designed, carried out and analyzed data from most of the experiments and wrote the manuscript with input from all co-authors; S.R. performed experiments; R.-M.L. and M.D. designed experiments and interpreted data; A.P.V. designed and analyzed data from experiments; J.C. provided mice, designed experiments, analyzed and interpreted data, and revised the manuscript; J.W.C. and D.H.K. performed experiments; Y.P. and N.D. conceived the application of senescence removal to OA treatment and participated in in vivo experimental design; D.J.B. and J.M.v.D. carried out experiments on naturally occurring OA; J.H.E. conceived, designed and supervised the study, analyzed and interpreted data, and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Jennifer H Elisseeff.

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Competing interests

J.C., R.-M.L., Y.P., D.J.B. , J.M.v.D. , M.D., N.D. and J.H.E. own equity in Unity Biotechnology. Johns Hopkins University and Unity Biotechnology own intellectual property related to the research. O.H.J., C.K. and J.H.E. are inventors of Johns Hopkins University intellectual property licensed to Unity Biotechnology.

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Jeon, O., Kim, C., Laberge, RM. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23, 775–781 (2017). https://doi.org/10.1038/nm.4324

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