Research progress of cellular senescence in the pathogenesis of osteoarthritis_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

XIE Jinwei ^1,2,3 , LU Lingyun ^2,4 ,  YU Xijie ^2,5

1. Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;
2. Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;
3. National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;
4. Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;
5. Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;

Corresponding author：

YU Xijie, Email: xijieyu@hotmail.com

Keywords：

Osteoarthritis; cellular senescence; cartilage cells; cell rejuvenation

DOI：

10.7507/1002-1892.202011065

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the pathological effects of cellular senescence in the occurrence and development of osteoarthritis (OA) and potential therapeutic targets.Methods The role of chondrocyte senescence, synovial cell senescence, mesenchymal stem cells senescence in OA, and the biological mechanism and progress of chondrocyte senescence were summarized by consulting relevant domestic and abroad literature.Results The existing evidence has basically made clear that chondrocyte senescence, mesenchymal stem cells senescence, and cartilage repair abnormalities, and the occurrence and development of OA have a certain causal relationship, and the role of the senescence of synovial cells, especially synovial macrophages in OA is still unclear. Transcription factors and epigenetics are the main mechanisms that regulate the upstream pathways of cellular senescence. Signal communication between cells can promote the appearance of senescent phenotypes in healthy cells. Targeted elimination of senescent cells and promotion of mesenchymal stem cells rejuvenation can effectively delay the progress of OA.Conclusion Cellular senescence is an important biological phenomenon and potential therapeutic target in the occurrence and development of OA. In-depth study of its biological mechanism is helpful to the early prevention and treatment of OA.

Citation： XIE Jinwei, LU Lingyun, YU Xijie. Research progress of cellular senescence in the pathogenesis of osteoarthritis. Chinese Journal of Reparative and Reconstructive Surgery, 2021, 35(4): 519-526. doi: 10.7507/1002-1892.202011065 Copy

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1. Glyn-Jones S, Palmer AJ, Agricola R, et al. Osteoarthritis. Lancet, 2015, 386(9991): 376-387.
2. Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis, 2014, 73(7): 1323-1330.
3. 王欢, 孙贺, 张耀南, 等. 中国 40 岁以上人群原发性膝骨关节炎各间室患病状况调查. 中华骨与关节外科杂志, 2019, 12(7): 528-532.
4. Wallace IJ, Worthington S, Felson DT, et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci U S A, 2017, 114(35): 9332-9336.
5. 王锴, 董雪, 林剑浩. 膝关节骨关节炎患者疾病医疗费用的调查. 中华医学杂志, 2017, 97(1): 29-32.
6. Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol, 2014, 15(7): 482-496.
7. Childs BG, Durik M, Baker DJ, et al. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med, 2015, 21(12): 1424-1435.
8. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol, 2018, 28(6): 436-453.
9. Vinatier C, Domínguez E, Guicheux J, et al. Role of the inflammation-autophagy-senescence integrative network in osteoarthritis. Front Physiol, 2018, 9: 706.
10. Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov, 2017, 16(10): 718-735.
11. van Deursen JM. The role of senescent cells in ageing. Nature, 2014, 509(7501): 439-446.
12. Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer, 2015, 15(7): 397-408.
13. Wiley CD, Flynn JM, Morrissey C, et al. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell, 2017, 16(5): 1043-1050.
14. Lee BY, Han JA, Im JS, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell, 2006, 5(2): 187-195.
15. Althubiti M, Lezina L, Carrera S, et al. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis, 2014, 5: e1528.
16. Li Y, Zhao H, Huang X, et al. Embryonic senescent cells re-enter cell cycle and contribute to tissues after birth. Cell Res, 2018, 28(7): 775-778.
17. Storer M, Mas A, Robert-Moreno A, et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell, 2013, 155(5): 1119-1130.
18. Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell, 2014, 31(6): 722-733.
19. Helman A, Klochendler A, Azazmeh N, et al. p16 (Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med, 2016, 22(4): 412-420.
20. He S, Sharpless NE. Senescence in health and disease. Cell, 2017, 169(6): 1000-1011.
21. Appleton CT. Osteoarthritis year in review 2017: biology. Osteoarthritis Cartilage, 2018, 26(3): 296-303.
22. Prieto-Alhambra D, Judge A, Javaid MK, et al. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis, 2014, 73(9): 1659-1664.
23. Gao SG, Zeng C, Li LJ, et al. Correlation between senescence-associated beta-galactosidase expression in articular cartilage and disease severity of patients with knee osteoarthritis. Int J Rheum Dis, 2016, 19(3): 226-232.
24. Xu M, Bradley EW, Weivoda MM, et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A Biol Sci Med Sci, 2017, 72(6): 780-785.
25. Jeon OH, 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, 2017, 23(6): 775-781.
26. Loeser RF, Collins JA, Diekman BO. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol, 2016, 12(7): 412-420.
27. Ashraf S, Cha BH, Kim JS, et al. Regulation of senescence associated signaling mechanisms in chondrocytes for cartilage tissue regeneration. Osteoarthritis Cartilage, 2016, 24(2): 196-205.
28. Diekman BO, Sessions GA, Collins JA, et al. Expression of p16 (INK) (4a) is a biomarker of chondrocyte aging but does not cause osteoarthritis. Aging Cell, 2018, 17(4): e12771.
29. Effenberger T, von der Heyde J, Bartsch K, et al. Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding. FASEB J, 2014, 28(11): 4847-4856.
30. Jeon OH, Wilson DR, Clement CC, et al. Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers. JCI Insight, 2019, 4(7): e125019.
31. Feng M, Peng H, Yao R, et al. Inhibition of cellular communication network factor 1 (CCN1)-driven senescence slows down cartilage inflammaging and osteoarthritis. Bone, 2020, 139: 115522.
32. Varela-Eirin M, Varela-Vazquez A, Guitian-Caamano A, et al. Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis. Cell Death Dis, 2018, 9(12): 1166.
33. Glück S, Guey B, Gulen MF, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol, 2017, 19(9): 1061-1070.
34. Dou Z, Ghosh K, Vizioli MG, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature, 2017, 550(7676): 402-406.
35. Overhoff MG, Garbe JC, Koh J, et al. Cellular senescence mediated by p16INK4A-coupled miRNA pathways. Nucleic Acids Res, 2014, 42(3): 1606-1618.
36. Munk R, Panda AC, Grammatikakis I, et al. Senescence-associated MicroRNAs. Int Rev Cell Mol Biol, 2017, 334: 177-205.
37. Philipot D, Guérit D, Platano D, et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res Ther, 2014, 16(1): R58.
38. Guan YJ, Li J, Yang X, et al. Evidence that miR-146a attenuates aging- and trauma-induced osteoarthritis by inhibiting Notch1, IL-6, and IL-1 mediated catabolism. Aging Cell, 2018, 17(3): e12752.
39. Grillari J, Hackl M, Grillari-Voglauer R. miR-17-92 cluster: ups and downs in cancer and aging. Biogerontology, 2010, 11(4): 501-506.
40. de Pontual L, Yao E, Callier P, et al. Germline deletion of the miR-17~92 cluster causes skeletal and growth defects in humans. Nat Genet, 2011, 43(10): 1026-1030.
41. Mirzamohammadi F, Kozlova A, Papaioannou G, et al. Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models. Nat Commun, 2018, 9(1): 1352.
42. Salih DA, Brunet A. FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol, 2008, 20(2): 126-136.
43. Rached MT, Kode A, Xu L, et al. FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metab, 2010, 11(2): 147-160.
44. Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell, 2004, 117(3): 399-412.
45. Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 2017, 169(1): 132-147.
46. Fisch KM, Gamini R, Alvarez-Garcia O, et al. Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis. Osteoarthritis Cartilage, 2018, 26(11): 1531-1538.
47. Akasaki Y, Hasegawa A, Saito M, et al. Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis. Osteoarthritis Cartilage, 2014, 22(1): 162-170.
48. Matsuzaki T, Alvarez-Garcia O, Mokuda S, et al. FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis. Sci Transl Med, 2018, 10(428): eaan0746.
49. Culemann S, Grüneboom A, Nicolás-Ávila JÁ, et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature, 2019, 572(7771): 670-675.
50. Zhang Y, Zhou S, Cai W, et al. Hypoxia/reoxygenation activates the JNK pathway and accelerates synovial senescence. Mol Med Rep, 2020, 22(1): 265-276.
51. Hall BM, Balan V, Gleiberman AS, et al. p16 (Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging (Albany NY), 2017, 9(8): 1867-1884.
52. Hall BM, Balan V, Gleiberman AS, et al. Aging of mice is associated with p16 (Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY), 2016, 8(7): 1294-1315.
53. Covarrubias AJ, Kale A, Perrone R, et al. Senescent cells promote tissue NAD⁺ decline during ageing via the activation of CD38⁺ macrophages. Nat Metab, 2020, 2(11): 1265-1283.
54. Čamernik K, Mihelič A, Mihalič R, et al. Increased exhaustion of the subchondral bone-derived mesenchymal stem/stromal cells in primary versus dysplastic osteoarthritis. Stem Cell Rev Rep, 2020, 16(4): 742-754.
55. Ha CW, Park YB, Kim SH, et al. Intra-articular mesenchymal stem cells in osteoarthritis of the knee: A systematic review of clinical outcomes and evidence of cartilage repair. Arthroscopy, 2019, 35(1): 277-288.
56. Cao X, Luo P, Huang J, et al. Intraarticular senescent chondrocytes impair the cartilage regeneration capacity of mesenchymal stem cells. Stem Cell Res Ther, 2019, 10(1): 86.
57. Malaise O, Tachikart Y, Constantinides M, et al. Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development. Aging (Albany NY), 2019, 11(20): 9128-9146.
58. Huang J, Chen C, Liang C, et al. Dysregulation of the Wnt signaling pathway and synovial stem cell dysfunction in osteoarthritis development. Stem Cells Dev, 2020, 29(7): 401-413.
59. Mazzotti E, Teti G, Falconi M, et al. Age-related alterations affecting the chondrogenic differentiation of synovial fluid mesenchymal stromal cells in an equine model. Cells, 2019, 8(10): 1116.
60. Neybecker P, Henrionnet C, Pape E, et al. Respective stemness and chondrogenic potential of mesenchymal stem cells isolated from human bone marrow, synovial membrane, and synovial fluid. Stem Cell Res Ther, 2020, 11(1): 316.
61. Neri S, Guidotti S, Lilli NL, et al. Infrapatellar fat pad-derived mesenchymal stromal cells from osteoarthritis patients: In vitro genetic stability and replicative senescence. J Orthop Res, 2017, 35(5): 1029-1037.
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Research progress of cellular senescence in the pathogenesis of osteoarthritis

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