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
D Noël
Université de Montpellier
daniele.noel@inserm.fr
Meet the Team
Université de Montpellier
Université Pierre et Marie Curie
Université Pierre et Marie Curie
Hospital Teresa Herrera
Arthritis Courtin Fondation
Université de Nantes
Université de Nantes
Centre Universitaire des Saints-Pères
Radboud UMC
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.
Final Results
With the increasing evidence that many ageing-associated diseases such as osteoarthritis (OA) are associated with senescence, it was hypothesized that removing senescent cells from our organs could increase the lifespan. The SEN-OA project therefore aimed at evaluating whether senescence targeting might be a therapeutic strategy for OA.
We have detected a high number of senescent cells in the joint compartments, particularly in cartilage, that confirm that senescent cells accumulate with age and in severe OA grades. This was associated with the dysregulation of several targets that are responsible for tissue maintenance. We provided evidence that mesenchymal stromal cells and their extracellular vesicles can protect the cartilage cells to enter senescence and regulate the production of the components of the cartilage matrix. A number of molecules able to kill senescent cells and to improve OA symptoms have been identified and one of these, Fenofibrate, is now being tested in the clinics.
Lay Summary
With the increasing evidence that many ageing-associated diseases such as osteoarthritis (OA) are associated with cellular senescence, it was hypothesized that removing senescent cells from our body or organs could increase the healthspan (the length of time spent free of serious illness) and lifespan. The SEN-OA project therefore aimed at evaluating whether senescence targeting might be a therapeutic strategy for OA patients and at identifying novel compounds acting on senescence-associated processes.
We have detected a high number of senescent cells in the joint compartments, particularly in cartilage, using both human samples and animal models of OA that confirm that senescent cells accumulate with age and in the most severe OA grades. This was associated with the dysregulation of several emerging targets that are responsible for tissue maintenance and their modulation was sufficient to protect cartilage from damage. In the search of possible therapeutic options, we provided evidence that mesenchymal stromal cells and their extracellular vesicles can protect the cartilage cells to enter senescence and regulate the production of the components of the cartilage matrix. A number of molecules able to kill senescent cells and to improve OA symptoms have been identified and one of these, Fenofibrate, a repurposing molecule is now being tested in the clinics. Furthermore, a new chemical entities (NCE) screening effort was performed to identify novel senolytics to treat OA.
With 30 million Europeans who suffer from severe OA for whom there are no curative treatments, we have the hope to develop an innovative treatment for those patients.
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.
Read more - Delplace V, Boutet MA, Le Visage C, Maugars Y, Guicheux J, Vinatier C. Osteoarthritis: From upcoming treatments to treatments yet to come. Joint Bone Spine. 2021 Oct;88(5):105206. doi: 10.1016/j.jbspin.2021.105206. Epub 2021 May 4. PMID: 33962030.
Read more - Boulestreau, Veret, D., Brondello, J.-M., & Noel, D. (2021). La senescence : de son implication physiopathologique aux traitements futurs/Senescence: From physiopathology to future treatments. Revue du rhumatisme monographies, 88(2), 87–. https://doi.org/10.1016/j.monrhu.2020.12.007
Read more - 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.
Read more - Boulestreau J, Maumus M, Rozier P, Jorgensen C and Noël D (2020) Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging. Frontiers in Cell and Developmental Biology. 8:107. doi: 10.3389/fcell.2020.00107
Read more - 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.
Read more - 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.
Read more - 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.
Read more - Vinatier C, Domínguez E, Guicheux J, Caramés B. Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis. Front Physiol. 2018; 25; 9: 706.
Read more
EULAR Abstracts
2021
- POS0375: 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.
- POS0374: 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
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)