p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodelling in osteoarthritis.

Abstract : INTRODUCTION: Recent evidence suggests that tissue accumulation of senescent p16INK4a positive cells during lifespan would be deleterious for tissue functions and could be the consequence of the inherent age-associated disorders. Osteoarthritis (OA) is characterized by the accumulation of chondrocytes expressing p16INK4a and markers of the senescence-associated secretory phenotype (SASP) including the matrix remodelling metallo-proteases MMP1/MMP13 and pro-inflammatory cytokines IL-8, IL-6. Here we evaluated the role of p16INK4a in the OA-induced SASP and its regulation by microRNAs (miRs). METHODS: We used IL-1beta-treated primary OA chondrocytes cultured in 3D or mesenchymal stem cells (MSC) differentiated into chondrocyte to follow p16INK4a expression. By transient transfection experiments and the use of knock out mice we validate p16INK4a function in chondrocytes and its regulation by one miR identified by means of a genome wide miR-arrays analysis. RESULTS: p16INK4a is induced upon IL-1beta treatment and also during in vitro chondrogenesis. In mouse model, Ink4a locus favors in vivo the proportion of terminally differentiated chondrocytes. When overexpressed in chondrocytes, p16INK4a is sufficient to induce the production of the two matrix remodelling enzymes, MMP1 and MMP13, thus linking senescence with OA pathogenesis and bone development. We identified miR-24, as a negative regulator of p16INK4a. Accordingly, p16INK4a expression increased while miR-24 level was repressed upon IL-1beta addition, in OA cartilage and during in vitro terminal chondrogenesis. CONCLUSIONS: We disclosed herein a new role of the senescence marker p16INK4a and its regulation by miR-24 during OA and terminal chondrogenesis.
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Submitted on : Thursday, April 24, 2014 - 5:07:04 PM
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Didier Philipot, David Guérit, Daniela Platano, Paul Chuchana, Eleonora Olivotto, et al.. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodelling in osteoarthritis.. Arthritis Research and Therapy, BioMed Central, 2014, 16 (1), pp.R58. ⟨10.1186/ar4494⟩. ⟨inserm-00983071⟩

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