Many of us wake up stiff in the morning and find it difficult to move, or we often experience knee pain and difficulty walking up and down stairs. These symptoms we think of as signs of "getting old" are actually a medical condition called osteoarthritis (OA). Osteoarthritis is caused by the aging and damage of cartilage tissue in the joints. In a paper published this month in the journal Aging Cell, a team of researchers from the University of Southern California (USC) found that signal transduction and transcriptional activation protein 3 (STAT3) is associated with the progression of osteoarthritis and is key to rejuvenating aging cartilage.


STAT3 is expressed in tissues throughout the body and is involved in a variety of reactions, including cell growth and death, immune system regulation, and bone tissue breakdown. Previous studies have shown that STAT3 seems to play a contradictory role in the occurrence of osteoarthritis. On the one hand, STAT3 can promote inflammation and lead to disease deterioration; on the other hand, STAT3 is closely related to tissue regeneration. To understand the role STAT3 plays in chondrocytes, the researchers conducted a series of experiments and found that STAT3 is key to controlling the cells' "aging clock."

Epigenetic regulation is the mechanism cells use to turn gene expression on or off. The researchers found that aging and developing young chondrocytes have different epigenetic maps, which means that changing the epigenetic map can change the age of chondrocytes. STAT3 is the mechanism that controls this mechanism. The scientists found that activating STAT3 with small molecules turned on the expression of many genes and produced the epigenetic map typical of young chondrocytes. Conversely, when STAT3 expression is genetically inhibited, many genes in the cells are turned off, promoting the formation of the epigenetic map that is characteristic of aging chondrocytes. It was found that the regulatory mechanism of STAT3 may be through DNMT3B protein which interacts with it. When STAT3 was inactivated, the expression and activity of DNMT3B increased, and many aging markers were added to DNA, thus promoting the progression of knee osteoarthritis in injured mice.
However, it's not that making chondrocytes younger is better for treating osteoarthritis. In fact, a cluster of young regenerated cells was found in the cartilage of mice with knee osteoarthritis, which is common during embryonic development or acute injury. However, these young cells are not mature enough to promote the formation of non-functioning, immature cartilage in chronic conditions such as osteoarthritis. Over time, highly activated, immature mechanisms in these chondrocytes promote inflammatory responses and ultimately lead to tissue degeneration and fibrosis.

"STAT3 plays multiple roles in tissue formation, regeneration, inflammation and cancer. In this study, we found that we can reverse the age of joint forming cells through chemical molecules, which has great clinical translational potential." USC Professor Denis Evseenko, PhD, co-corresponding author of the paper. Therefore, in the future, how to use STAT3 to promote chondrocyte rejuvenation while avoiding inflammatory response is the key to develop STAT3-based therapies to improve osteoarthritis. Let us hope that scientists will be able to further understand the regulatory mechanisms of STAT3 and facilitate the development of more effective treatments for osteoarthritis.
Reference materials:
[1] Sarkar, Arijita et al. "STAT3 promotes a youthful epigenetic state in articular chondrocytes." Aging cell, e13773.13 Jan.2023, doi:10.1111/acel.13773
[2] How to rewind the clock on arthritic cartilage... stat!  Retrieved January 24, 2023 from https://stemcell.keck.usc.edu/rewind-clock-on-arthritic-cartilage/
[3] Protein turns back clock in cartilage cells,  could have therapeutic potential for osteoarthritis. Retrieved January 24,  2023 from  https://www.fiercebiotech.com/research/protein-turns-back-clock-cartilage-cells-could-have-therapeutic-potential-osteoar thritis

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