University of Pittsburgh researchers have developed a novel therapy for chondrocyte aging and, ultimately, osteoarthritis (OA). Transcriptomic analysis has identified the transcriptome factor, GATA binding protein 4 (GATA4) is associated with aging. A small molecule, HCA42027, can reduce expression of GATA4 in chondrocytes restoring their ability to create new cartilage. This novel therapeutic strategy could offer hope to millions impacted daily by OA through pain and decreased quality of life.
HCA42027, (2-[(2H-1,3-Benzodioxol-5-yl)methyl] butanedioic acid) can suppress GATA4 expression in old chondrocytes can restore the regenerative ability of chondrocytes. Treatment with HCA42047 led to increased aggrecan and collagen type II production and could be a novel therapeutic approach for OA.
Description
Over 32 million Americans are currently living with OA, with an estimated 250 million affected globally. Resulting from cartilage damage, OA is the most common form of degenerative disease globally, impacting on joint and limb movement along with pain and stiffness. OA can severely impact on quality of life of older adults through limiting their daily and social activities. Currently, no disease-modifying OA therapies are approved for use in patients, with lifestyle interventions and symptom management used to reduce the impact of the disease. With a growing aging population, there is a pressing need to develop treatment strategies for OA. This novel approach uses suppression of GATA4 to restore the ability of old chondrocytes to repair cartilage and could be a restorative therapy for OA patients.
Applications
• Osteoarthritis
• Atherosclerosis
• Heart Failure
Advantages
A well-established link between aging and OA has been established; however, a complete understanding of the underlying mechanism has yet to be established. Cartilage degradation is a central feature. In healthy adults, chondrocytes repair damaged cartilage, but with aging the regenerative ability of chondrocytes declines.
Using transcriptomic analysis, the impact of GATA4 expression on chondrocyte activity has been discovered. GATA4 overexpression leads to reduced cartilage-forming capacity and induces upregulation of pro-inflammatory cytokines. This approach uses this knowledge with a small molecule, HCA42027, to suppress GATA4 expression of GATA4 in aged chondrocytes. A variety of other aging diseases (e.g., atherosclerosis) are also associated with GATA4 overexpression and this novel strategy could have wide applications in gerontology.
Invention Readiness
RNA sequencing of young and old human and animal chondrocytes demonstrated GATA4 levels were higher in older cells. Induced animal models of OA confirmed poorer outcomes (e.g., pain) when GATA4 was overexpressed compared with controls. Suppression GATA4 expression in old chondrocytes restored the regenerative abilities of old chondrocytes.
IP Status
Patent Pending
Related Publication(s)
Makarczyk, M. J., Zhang, Y., Aguglia, A., Bartholomew, O., Hines, S., Suyash Sinkar, Liu, S., Duvall, C., & Lin, H. (2025). Aging-associated Increase of GATA4 levels in Articular Cartilage is Linked to Impaired Regenerative Capacity of Chondrocytes and Osteoarthritis. BioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.7554/elife.106224.1
Makarczyk, M., Zhang, Y., Bartholomew, O., Hines, S., & Lin H. (2025). Aging-associated Increase of GATA4 levels in Articular Cartilage is Linked to Impaired Regenerative Capacity of Chondrocytes and Osteoarthritis. Osteoarthritis Cartilage. https://doi.org/10.1016/j.joca.2025.02.556
