Eliminating senescent chondrogenic progenitor cells enhances chondrogenesis under intermittent hydrostatic pressure for the treatment of OA

BACKGROUND: Osteoarthritis (OA) is a major cause of limb dysfunction, and distraction arthroplasty which generates intermittent hydrostatic pressure (IHP) is an effective approach for OA treatment. However, the result was not always satisfactory and the reasons remained unresolved. Because aging is recognized as an important risk factor for OA and chondrogenic progenitor cells (CPCs) could acquire senescent phenotype, we made a hypothesis that CPCs senescence could have harmful effect on chondrogenesis and the outcome of distraction arthroplasty could be improved by eliminating senescent CPCs pharmacologically. METHODS: The role of senescent CPCs on distraction arthroplasty was first determined by comparing the cartilage samples from the failure and non-failure patients. Next, the biological behaviors of senescent CPCs were observed in the in vitro cell culture and IHP model. Finally, the beneficial effect of senescent CPCs clearance by senolytic dasatinib and quercetin (DQ) on cartilage regeneration was observed in the in vitro and in vivo IHP model. RESULTS: Larger quantities of senescent CPCs along with increased IL-1 β secretion were demonstrated in the failure patients of distraction arthroplasty. Senescent CPCs revealed impaired proliferation and chondrogenic capability and also had increased IL-1 β synthesis, typical of senescence-associated secretory phenotype (SASP). CPCs senescence and SASP formation were mutually dependent in vitro. Greater amounts of senescent CPCs were negatively correlated with IHP-induced chondrogenesis. In contrast, chondrogenesis could be significantly improved by DQ pretreatment which selectively induced senescent CPCs into apoptosis in the in vitro and in vivo IHP model. Mechanistically, senescent CPCs elimination could decrease SASP formation and therefore promote the proliferation and chondrogenic regeneration capacity of the surrounding survived CPCs under IHP stimulation. CONCLUSIONS: Eliminating senescent CPCs by senolytics could decrease SASP formation and improve the result of joint distraction arthroplasty effectively. Our study provided a novel CPCs senescence-based therapeutic target for improving the outcome of OA treatment.