SEN-OA – Targeting senescent cells in osteoarthritis: an innovative therapeutic approach

Concept

The main risk factor for Osteoarthritis (OA) is ageing. An emerging concept for age-related diseases is that senescent cells accumulate with time and release SASP (senescence-associated secretory profile) products, which alter tissue functions. Accumulation of senescent cells during lifespan is believed to contribute to progressive tissue loss of functions. Specific elimination of these cells could prevent some age-associated diseases.

Facts and figures

Project lead
D Noël
Université de Montpellier
daniele.noel@inserm.fr
FOREUM research grant: € 600.000
2018–2021

Meet the team

D Noël
Université de Montpellier
C Jorgensen
Université de Montpellier
X Houard
Université Pierre et Marie Curie
F Berenbaum
Université Pierre et Marie Curie
C Caramés Perez
Hospital Teresa Herrera
L Comole
Arthritis Courtin Fondation
J Guicheux
Université de Nantes
C Vinatier
Université de Nantes
F Rannou
Centre Universitaire des Saints-Pères
P van der Kraan
Radboud UMC

Objectives

We propose a multifaceted approach combining innovative biomedical senescence models, ageing animal studies, human sample analyses and screening for senescence-targeting compounds for clinical application to (i) decipher the role of ageing-associated senescence mechanisms in the appearance of OA and (ii) develop innovative treatments for OA patients. If successful, the project could lead to a first- in-man clinical trial.

Patient voice

We have discussed the proposal with a patient group in Paris, they thought the idea novel and worthwhile. We gained their input to the lay summary. We will have two patient representatives to support the writing of our patient information sheets and to help communicate the findings of the project. They will participate to the scientific advisory board. There are no obvious risks of the project to the patients. Technical risk is minimal as the assays involved are already carried out in our laboratories.

Interim results

  • WP1. A movie dedicated to the presentation of the SEN-OA project has been made. A round table on the role of patients in research projects has been organized with one of the patient expert and Fondation Arthritis at the 1st French Congress on Regenerative Medicine and Biotherapies in Montpellier (October 2020)
  • WP2. Several senescence markers have been validated by immunohistology on different articular samples from murine models and human with OA. A bio-collection of human OA tissues has been implemented.
  • WP3. Direct modulation of p16INK4A was shown to partially protect mice from developing OA and a model of senescence in zebrafish was generated to investigate the impact of senolytics. Mesenchymal stromal cells and their derived extracellular vesicles can protect from senescence induction in OA chondrocytes
  • WP4. A preliminary screening was performed with a repurposing library to identify Senolytics and Pro-autophagy modulators in human chondrocytes. Validation of several candidates is ongoing.

Publications

  • Vianney Delplace, Marie-Astrid Boutet, Catherine Le Visage, Yves Maugars, Jérôme Guicheux, Claire Vinatier. Arthrose : des traitements à venir aux traitements d’avenir. Revue du Rhumatisme, 2021.
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  • Maumus M, Rozier P, Boulestreau J, Jorgensen C, Noël D. Mesenchymal stem cell derived extracellular vesicles: opportunities and challenges for clinical translation. Front Bioeng Biotechnology, 2020, 8:997.
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  • Boulestreau J, Maumus M, Rozier P, Jorgensen C, Noël D. Mesenchymal stem cell derived extracellular vesicles in aging. Frontiers in Cell and Developmental Biology, 2020; 8: 107
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  • Malaise O, Tachikart Y, Constantinides M, Mumme M, Ferreira-Lopez R, Noack S, Krettek C, Noël D, Wang J, Jorgensen C, Brondello JM. Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development. Aging (Albany NY) 2019; 11(20): 9128-9146.
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  • Tachikart Y, Malaise O,  Mumme M, Jorgensen C, Brondello JM. Seno-suppressive molecules as new therapeutic perspectives in rheumatic diseases; Biochem Pharmacol 2019; 165: 126-133.
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  • Nogueira-Recalde U, Lorenzo-Gómez I, Blanco FJ, Loza MI, Grassi D, Shirinsky V, Shirinsky I, Lotz M, Robbins PD, Domínguez E, Caramés B. Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine 2019; 45: 588-605.
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  • Vinatier C, Domínguez E, Guicheux J, Caramés B. Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis. Front Physiol. 2018; 25; 9: 706.
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EULAR Abstracts

2021

  • Irene Lorenzo Gómez, Uxía Nogueira-Recalde, Natividad Oreiro, Jose A. Pinto-Tasende, Martin Lotz , Francisco J. Blanco, Beatriz Caramés. Chaperone-mediated Autophagy is a Hallmark of Joint Disease in Osteoarthritic Patients. 2021.
  • Boulestreau J, Maumus M, Rozier P, Jorgensen C, Noël D. Senescence did not alter the chondroprotective effect of extracellular vesicles from mesenchymal stromal cells. 2021

Go to EULAR Abstract Archive

Abstracts to other meetings

2021

  • M. Georget, N. Bon, C. Vignes, J. Lesoeur, C.  Boyer, A. Defois, B. Bodic, G. Grimandi, J. Guicheux, C. Vinatier. In vitro and in vivo characterisation of senescence markers in osteoarthritis. 2021
  • Boulestreau J, Maumus M, Rozier P, Jorgensen C, Noël D. Senescence did not alter the chondroprotective effect of extracellular vesicles from adipose mesenchymal stem cells in osteoarthritis. OARSI, 2021 (oral)
  • Boulestreau J, Maumus M, Rozier P, Jorgensen C, Noël D. Senescence did not alter the chondroprotective effect of extracellular vesicles from mesenchymal stem cells. ISCT, 2021 (poster)
  • Boulestreau J, Maumus M, Rozier P, Jorgensen C, Noël D. Senescence did not alter the chondroprotective effect of extracellular vesicles from adipose mesenchymal stem cells in osteoarthritis. ISEV, 2021 (oral)