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nature portfolio journals permissions reprints nature portfolio privacy policy advertising kirby research center social media runx2-dependent bone development nature+ nature 509 nature 479 nature 530 nature photoreactive adhesive–hydrogel composite oarsi histopathology initiative—recommendations research intellectual property related age-related pathologies1 naturally occurring oa author correspondence p16-3mr transgenic mouse permissions springerlink instant access senescence-induced senescence increases healthy lifespan8 increased cartilage development european economic area remi-martin laberge targeting dna damage human cartilage repair privacy van den berg senescent cells attenuates johns hopkins university extracellular vesicles enriched chronic disease characterized bloomberg-kimmel institute subscription content synovial cells contributing matrix remodeling p53-dependent release temporomandibular joint osteoarthritis cartilage tissue isolated p16ink4a–rb pathway human term placenta issue learn chondrocyte terminal differentiation ulsan national institute explore content post-traumatic osteoarthritis

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         headline:Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment
         description:Pharmacological or genetic depletion of senescent cells in the joint ameliorates osteoarthritis in mice. 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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      headline:Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment
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      affiliation:
            name:Translational Tissue Engineering Center, Johns Hopkins University
            address:
               name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Do Hun Kim
      affiliation:
            name:Translational Tissue Engineering Center, Johns Hopkins University
            address:
               name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Yan Poon
      affiliation:
            name:Unity Biotechnology, Inc.
            address:
               name:Unity Biotechnology, Inc., Brisbane, USA
               type:PostalAddress
            type:Organization
      name:Nathaniel David
      affiliation:
            name:Unity Biotechnology, Inc.
            address:
               name:Unity Biotechnology, Inc., Brisbane, USA
               type:PostalAddress
            type:Organization
      name:Darren J Baker
      affiliation:
            name:Mayo Clinic College of Medicine
            address:
               name:Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, USA
               type:PostalAddress
            type:Organization
      name:Jan M van Deursen
      affiliation:
            name:Mayo Clinic College of Medicine
            address:
               name:Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, USA
               type:PostalAddress
            type:Organization
      name:Judith Campisi
      affiliation:
            name:Buck Institute for Research on Aging
            address:
               name:Buck Institute for Research on Aging, Novato, USA
               type:PostalAddress
            type:Organization
            name:Lawrence Berkeley National Laboratory, University of California, Berkeley, Berkley, California, USA.
            address:
               name:Lawrence Berkeley National Laboratory, University of California, Berkeley, Berkley, California, USA.,
               type:PostalAddress
            type:Organization
      name:Jennifer H Elisseeff
      affiliation:
            name:Translational Tissue Engineering Center, Johns Hopkins University
            address:
               name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
      name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
      name:Department of Chemistry, Ulsan National Institute of Science and Technology, Ulsan, South Korea
      name:Buck Institute for Research on Aging, Novato, USA
      name:Unity Biotechnology, Inc., Brisbane, USA
      name:Buck Institute for Research on Aging, Novato, USA
      name:European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
      name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
      name:Unity Biotechnology, Inc., Brisbane, USA
      name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
      name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
      name:Unity Biotechnology, Inc., Brisbane, USA
      name:Unity Biotechnology, Inc., Brisbane, USA
      name:Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, USA
      name:Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, USA
      name:Buck Institute for Research on Aging, Novato, USA
      name:Lawrence Berkeley National Laboratory, University of California, Berkeley, Berkley, California, USA.,
      name:Wilmer Eye Institute and the Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, USA
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