In a study from the University of Southern California and elsewhere, scientists found how a key protein called Signal Transducer and Activator of Transcription 3 (STAT3) might turn back the clock on aging cartilage that leads to osteoarthritis.
STAT3 performs an astonishing repertoire of roles in development and regeneration, as well as inflammatory disease and cancer.
In this study, the team found an innovative chemical approach for reversing the aging of joint-forming cells in a clinically relevant manner, because this intervention is simple and fully controlled.
They performed a series of experiments to uncover how STAT3 turns genes on and off through a process known as epigenetic regulation.
Specifically, the team identified patterns of epigenetic regulation that correlate with the age of cartilage cells.
These correlations served as the basis for creating what the researchers dubbed an “epigenetic clock” for cartilage cells.
The team used a molecule to activate STAT3 and were able to reverse the hands of the epigenetic clock—turning on many genes and creating an epigenetic pattern typical of younger cartilage cells.
When they genetically inactivated STAT3, the epigenetic clock ticked faster—turning off many genes and promoting an epigenetic pattern observed in older cartilage cells.
The scientists then focused their attention on an important enzyme called DNA methyltransferase 3 beta (DNMT3B), which interacts with STAT3.
When STAT3 was inactivated, DNMT3B kicked into high gear to add aging marks to the DNA molecule and promoted the progression of knee osteoarthritis in injured mice.
In the arthritic knee cartilage of the mice, the team found there was a big number of cartilage cells that appeared to be turning back time and reverting to an immature state.
The team says these cells may be assuming a more embryonic-like state as an attempt to enhance their capacity to develop new knee cartilage.
Unfortunately, while these immature cells make cartilage that is youthfully regenerative during embryonic development or acute injury, they seemed to create cartilage that is dysfunctionally immature in the context of a chronic condition such as osteoarthritis.
In the future, the results of this study can inform the quest to develop treatments that harness STAT3’s power to promote regeneration without tapping into its tendency to trigger inflammation.
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The study was conducted by Denis Evseenko et al and published in Aging Cell.
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