Abstract
BackgroundOsteoarthritis (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.MethodsThe 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.ResultsLarger 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.ConclusionsEliminating 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.
Highlights
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
Senescence of chondrogenic progenitor cells (CPCs) was associated with poor outcome of joint distraction arthroplasty in the treatment of endstage posttraumatic OA To determine whether CPCs aging had influence on the outcome of joint distraction arthroplasty, we collected cartilage samples from the patients subjected to ankle joint distraction arthroplasty
Cartilage regeneration was almost minimal in the failure patients as much more cartilage lesions and less-intensive staining of extracellular matrices was observed in the failure group as compared to the non-failure group (Fig. 1a)
Summary
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. 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. Removal of senescent chondrocytes genetically or pharmacologically could attenuate the OA disease [7], and transplantation of senescent chondrocytes into the normal joint could induce cartilage damage [8], suggesting that chondrocyte senescence could be a cell-level target for OA treatment. Senescent CPCs could be a potential cell-level target for OA treatment; the influence of CPCs senescence on the treatment of OA remains unknown
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