MSCs and tissue homeostasis:
impact of MSC aging and senescence on age-related disease onsets.
Epigenetic regulators such as microRNAs are involved in a number of biological functions such as proliferation, differentiation and cellular senescence.
Osteoarthritis (OA) is a common chronic degenerative disorder characterized by cartilage and bone lesions affecting more than 20% of the population older than 60 years of age. The heightened risk for development of primary OA with increasing age may be explained by age-related changes in chondrocytes.
Significant age-specific changes include decreased matrix synthesis, decreased anabolic response to growth factors and increased senescence (decline in DNA synthesis, acidic beta-galactosidase expression, telomere erosion, evidence for oxidative damage) (3). Senescence is induced by two overlapping cellular mechanisms. First, a cell intrinsic mechanism referred as telomere-dependent senescence characterized by telomere attrition at each cell division. The eroded telomeres are detected as DNA damage by the cell leading to a cell cycle arrest involving ATM/Chk2/p53/p21 checkpoint signalling pathway (4). The second, termed premature senescence, is induced by oxidative stress, specific growth conditions or oncogene expression, independently of telomere damage. In this case, growth arrest is mediated primarily by pRb-dependent pathway leading to the accumulation of p16ink4a, an inhibitor of cyclin D/Cdk4/6 complexes (5) but also by the ATM/Chk2/p53/p21 signalling pathway. Both telomere-dependent and -independent senescence pathways have been proposed to play a role in OA pathologies
Despite active research in the field, there remain challenges to understanding the complex processes linking OA pathogenesis and aging. Indeed, identification of new regulatory pathways will help to understanding how to modify the processes involved in OA. Among these, miRs and epigenetic enzymes are likely to play a role in modulating the role of the numerous molecular and cellular players acting in OA cartilage. Understanding the role of their expression will undoubtedly help developing new therapeutic approaches. The aim of the project is to understand the role of epigenetic regulators in the physiopathology of OA associated with chondrocyte premature senescence.
1. Kobayashi, T., Lu, J., Cobb, B. S., et al (2008) Proc Natl Acad Sci U S A 105, 1949-54
2. Barbarotto, E., Schmittgen, T. D., and Calin, G. A. (2008) Int J Cancer 122, 969-77
3. Brondello J. M, Philipot D, Djouad F, Jorgensen C, Noel, D. Open Rheumatol J. 2010 Feb 11;4:10-4.
4. Reaper, P. M., di Fagagna, F., and Jackson, S. P. (2004) Cell Cycle 3, 543-6
5. Jacobs, J. J., and de Lange, T. (2005) Cell Cycle 4, 1364-8
- Philipot D p16INK4a and its regulatory miR-24 link senescence and chondrocyte terminal differentiation associated matrix remodeling in osteoarthrtitis. (en révision)
- Guérit D et al. Sox9-regulated miRNA-574-3p inhibits chondrogenic differentiation of mesenchymal stem cells. PLoS One. 2013 Apr 23;8(4):e62582.
- Basbous J et al. Induction of ASAP (MAP9) contributes to p53 stabilization in response to DNA damage. Cell Cycle. 2012 Jun 15;11(12):2380-90.
- Brondello JM et al. Cellular senescence and the myth of Janus. Med Sci (Paris). 2012 Mar;28(3):288-96.
- Fritz V et al. Bone-metastatic prostate carcinoma favors mesenchymal stem cell differentiation toward osteoblasts and reduces their osteoclastogenic potential. J Cell Biochem. 2011 Nov;112(11):3234-45.
- Brondello JM et al. Cellular Senescence is a Common Characteristic Shared by Preneoplasic and Osteo-Arthritic Tissue. Open Rheumatol J. 2010 Feb 11;4:10-4.
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