Suppressing aging-associated increase of GATA4 levels to rejuvenate old chondrocytes

About This Grant

Abstract: The exposure of articular cartilage to excessive forces, combined with its limited ability to self-repair, can lead to chondral defects. If left untreated, these defects may initiate pathological changes in other joint components, ultimately resulting in osteoarthritis (OA). Importantly, the healing potential of cartilage decreases with aging. Specifically, chondrocytes, the primary cell type in cartilage, exhibit reduced anabolic activity and elevated catabolic responsiveness as they age. These changes are thought to significantly contribute to the development of age-related OA. Therefore, enhancing the intrinsic regenerative capacity of aging chondrocytes and improving their resilience to injury are critical to maintaining cartilage integrity and reducing the risk of OA in older populations. Currently, the mechanisms through which aging leads to detrimental changes in chondrocytes are not fully understood. As a result, there are no defined targets that can be utilized to enhance the quality of aged chondrocytes. To address this knowledge gap, we recently isolated healthy chondrocytes from the knee joints of young and old human donors who did not exhibit arthritis or any other joint disorders. We then performed Bulk RNA sequencing on these cells to analyze their transcriptomes. Interestingly, the unbiased upstream regulator analysis predicted GATA Binding Protein 4 (GATA4) is a key regulator of the aging process in chondrocytes. A validation study conducted with normal cartilage samples from mice and humans indicated an aging-associated increase in GATA4 protein levels in chondrocytes. More importantly, we discovered that overexpressing GATA4 in young, healthy human chondrocytes impaired cartilage formation and led to increased production of pro-inflammatory cytokines upon stimulation with transforming growth factor-beta 1 (TGFβ1). Conversely, the knockdown of GATA4 using siRNA, or suppressing GATA4 with a novel small-molecule inhibitor NSC140905 7, in old human chondrocytes enhanced their capacity to create hyaline cartilage. These exciting findings from our current studies support further investigation into whether suppressing GATA4 serves as an effective method for “rejuvenating” old chondrocytes, particularly in enhancing their regenerative potential and improving their capacity to withstand stressors. We hypothesize that suppressing GATA4 in aged chondrocytes can 1) enhance their capacity to generate hyaline-like cartilage in vivo, and 2) reduce injuries caused by various physiological stressors, particularly mechanical overloading. The success of this high-risk, high-reward project will shed light on the roles of GATA4 in chondrocytes and provide a new mechanism to explain aging-associated changes in chondrocytes. Additionally, this study will assess the effectiveness of reducing GATA4 levels as a novel approach to “rejuvenate” aged chondrocytes, specifically restoring their anabolic activities and reducing catabolic responsiveness.