Abstract
Tissue accumulation of p16INK4a-positive senescent cells is associated with age-related disorders, such as osteoarthritis (OA). These cell-cycle arrested cells affect tissue function through a specific secretory phenotype. The links between OA onset and senescence remain poorly described. Using experimental OA protocol and transgenic Cdkn2a+/luc and Cdkn2aluc/luc mice, we found that the senescence-driving p16INK4a is a marker of the disease, expressed by the synovial tissue, but is also an actor: its somatic deletion partially protects against cartilage degeneration. We test whether by becoming senescent, the mesenchymal stromal/stem cells (MSCs), found in the synovial tissue and sub-chondral bone marrow, can contribute to OA development. We established an in vitro p16INK4a-positive senescence model on human MSCs. Upon senescence induction, their intrinsic stem cell properties are altered. When co-cultured with OA chondrocytes, senescent MSC show also a seno-suppressive properties impairment favoring tissue degeneration. To evaluate in vivo the effects of p16INK4a-senescent MSC on healthy cartilage, we rely on the SAMP8 mouse model of accelerated senescence that develops spontaneous OA. MSCs isolated from these mice expressed p16INK4a. Intra-articular injection in 2-month-old C57BL/6JRj male mice of SAMP8-derived MSCs was sufficient to induce articular cartilage breakdown. Our findings reveal that senescent p16INK4a-positive MSCs contribute to joint alteration.
Highlights
Tissue homeostasis is ensured by the equilibrium between self-repair mechanisms of differentiated cells and their replacements through differentiation of tissue-specific adult stem cells [1]
Senescent cells are characterized by growth inhibition, functional www.aging-us.com changes, and the presence of the so-called senescenceassociated secretory phenotype (SASP) that includes the expression of inflammatory and trophic factors as well as tissue remodeling matrix metalloproteases (MMP) [2]
Www.aging-us.com revealed, even if not significant, a trend toward a higher bone surface/bone volume ratio and a lower subchondral bone volume in the medial compartment in SAMP8 mesenchymal stem cells (MSCs) injected mice (Figure 5F). These results demonstrate that senescent MSCs are sufficient to trigger alone cartilage and joint dysfunction in young wild-type mice, similar to the phenotypes observed in senescenceaccelerated SAMP8 mice and in human patients
Summary
Tissue homeostasis is ensured by the equilibrium between self-repair mechanisms of differentiated cells and their replacements through differentiation of tissue-specific adult stem cells [1]. Osteoarthritis (OA), the most common osteoarticular disease, is a consequence of progressive age-induced joint senescence, leading to cartilage degeneration, osteophytosis, sub-chondral bone remodeling and synovial hypertrophy or joint effusion [4, 5]. Joint cartilage relies on chondrocyte self-repair mechanisms, and on the autonomous and non-autonomous functions of the resident mesenchymal stem cells (MSCs). These nonhematopoietic CD34-, CD105+, CD90+, CD73+ cells are mainly found in sub-chondral bone marrow and the knee synovial tissue [6, 7]. In vitro and in vivo studies have shown that MSCs can form neocartilage and have remarkable tissue supportive functions through paracrine trophic factor production [8] and cell-to-cell direct contacts [9]
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