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Recent evidence suggests that tissue accumulation of senescent p16 INK4a -positive cells during the life span would be deleterious for tissue functions and could be the consequence of inherent age-associated disorders. Osteoarthritis (OA) is characterized by the accumulation of chondrocytes expressing p16 INK4a  and markers of the senescence-associated secretory phenotype (SASP), including the matrix remodeling metalloproteases MMP1/MMP13 and pro-inflammatory cytokines interleukin-8 (IL-8) and IL-6. Here, we evaluated the role of p16 INK4a  in the OA-induced SASP and its regulation by microRNAs (miRs).    Methods  We used IL-1-beta-treated primary OA chondrocytes cultured in three-dimensional setting or mesenchymal stem cells differentiated into chondrocyte to follow p16 INK4a  expression. By transient transfection experiments and the use of knockout mice, we validate p16 INK4a  function in chondrocytes and its regulation by one miR identified by means of a genome-wide miR-array analysis.    Results  p16 INK4a  is induced upon IL-1-beta treatment and also during  in vitro  chondrogenesis. In the mouse model,  Ink4a  locus favors  in vivo  the proportion of terminally differentiated chondrocytes. When overexpressed in chondrocytes, p16 INK4a  is sufficient to induce the production of the two matrix remodeling enzymes, MMP1 and MMP13, thus linking senescence with OA pathogenesis and bone development. We identified miR-24 as a negative regulator of p16 INK4a . Accordingly, p16 INK4a  expression increased while miR-24 level was repressed upon IL-1-beta addition, in OA cartilage and during  in vitro  terminal chondrogenesis.    Conclusions  We disclosed herein a new role of the senescence marker p16 INK4a  and its regulation by miR-24 during OA and terminal chondrogenesis.

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