Background/Purpose: Tissue accumulation of p16^INK4A-positive senescent cells is associated with age-related disorders such as osteoarthritis (OA). These senescent cells induce a tissue loss of function through a particular secretory phenotype called SASP (senescence-associated secretory phenotype). Links between OA onset and cellular senescence remain poorly detailed. We wanted to determine the presence of articular senescent cells in in vivo OA mouse models and study the involvement of mesenchymal stem cells (MSC) senescence in OA pathogenesis.

Methods: Wild-type mice C57BL/6, SAMP8/R1 (senescence accelerated mouse-prone and resistant), transgenic p16^{INK4A +/Luc}and p16^INK4ALuc/Lucwere used. Experimental OA was induced by intraarticular injections of collagenase (CIOA).

Results: (1) CIOA was induced in senescence-driven luciferase transgenic mice. Under CCD camera, a peak in luminescence was detected revealing the presence of senescent cells in the joint. Remarkably, articular senescence also contributes to OA: mice deficient in p16INK4a, a main senescence-driving known cell cycle inhibitor, were partially protected against CIOA. These results were confirmed in C57Bl/6 mice after CIOA by showing an increase in gene expression for senescence in the synovial tissue.
(2) MSCs found in synovial, cartilage, fat pad and bone marrow participate in joint homeostasis. Because MSC are at the root of OA development, we hypothesize that cellular senescence onset in these progenitors would be a possible etiological factor for OA. We stablished an in vitro p16^INK4A-induced senescence model on human MSC: their intrinsic properties (self-renewing and chondrogenesis) are altered when senescent. In co-culture conditions with chondrocytes from OA patients, senescent MSC lost their extrinsic chondroprotective properties.
(3) To in vivo challenge these findings, we rely on the mouse model of accelerated senescence SAMP8, which develop spontaneous OA at the age of 6 months with cartilage degradation, synovial hypertrophy, osteophytosis and subchondral bone remodelingassociated to meniscal calcification (micro-tomography). Isolated MSC from these mice express senescence (p16^INK4a, p21^waf1, MMP13, TGF-β1). Intra-articular injection of these isolated SAMP8-derived MSC compared to SAMR1-derived control MSC, in young wid-type C57Bl/6 mice, was suffisant by its own, to induce significant articular cartilage degradation (OA score of 12.2 ± 1.5 vs 6.1 ± 3.5 for SAMP8 and SAMR1 MSC respectively. p < 0.05).

Conclusion: p16^INK4A-induced cellular senescence in MSC played a causative role in cartilage loss of function and OA pathogeny. In vitro, senescent MSC show altered intrinsic and extrinsic supportive tissue functions.In vivo, intra-articular injection of senescent MSC induced cartilage degradation. Specific targeting of such deleterious senescent cells could be an innovating and promising treatment in OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mesenchymal-stem-cell-senescence-alleviates-their-chondrogenic-and-seno-suppressive-properties-contributing-to-osteoarthritis-development/