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Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis in mice. Targeted knockout (KO) of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP deficiency led to the down-regulation of FOXD1. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vector encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential therapeutic target for gene therapy to alleviate osteoarthritis.
This article was published in the following journal.
Name: PLoS biology
CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human...
Forkhead box D1 (FOXD1) has a well-established role in early embryonic development and organogenesis and functions as an oncogene in several cancers. However, the clinical significance and biological ...
Senescence is a stress-responsive cellular program that leads to cell cycle arrest. In cancer cells, senescence has profound implications for tumor aggressiveness and clinical outcome, but the molecul...
FOXD1, one of the transcription factors of the FOX family, has been shown to be important for mammalian reproduction but little is known about its function in avian species. In the present study, we i...
Senescence is a multistep cellular program featuring a stable cell cycle arrest, which occurs upon exposure to various stressors. Senescent cells exhibit metabolic activity and hypertrophy and produce...
This is an exploratory non-drug, interventional biomarker study in approximately 30 eligible patients with active osteoarthritis to investigate the degree of senescence-associated disease....
The aim of the study is to investigate the impact of Anti-Thymocyte Globulin (ATG) on immune senescence. Markers of immune senescence expression is assessed in a prospective cohort of rena...
Circulatory shocks (CS) are life-threatening, acute organ dysfunction. Advances in critical care medicine have decreased early hospital mortality, increasing the number of surviving patien...
Patients with cancer often complain that their "mind does not seem to be clear." This can be due to stress, depression, anxiety, or physical problems caused by cancer or the treatments use...
The study goal is to assess the effect of senescent cell clearance on senescence burden, physical ability or frailty, and adipose tissue-derived mesenchymal stem cell (MSC) functionality i...
Process by which cells irreversibly stop dividing and enter a state of permanent growth arrest without undergoing CELL DEATH. Senescence can be induced by DNA DAMAGE or other cellular stresses, such as OXIDATIVE STRESS.
Changes in the organism associated with senescence, occurring at an accelerated rate.
The branch of medicine concerned with the physiological and pathological aspects of the aged, including the clinical problems of senescence and senility.
Physicians specializing in physiological and pathological aspects of aging and the aged, including the clinical problems of senescence and senility.
An IBUPROFEN-type anti-inflammatory analgesic and antipyretic. It is used in the treatment of rheumatoid arthritis and osteoarthritis.
Arthritis is by definition the inflammation of one or more joints, characterized by swelling, pain, warmth, redness and diminished range of joint movement (Oxford Medical Dictionary). There are many different types; Noninflammatory; Osteoarthritis, N...