In the Cell journal iScience, researchers have published their discovery of a protein that inhibits osteoarthritis in mice by diminishing fatty acid production.
Fats in the wrong place
Previous work has found a strong link between obesity and osteoarthritis of the knee [1]. While the increased weight itself may be a factor, fatty acids themselves are linked to arthritis in the knee [2]. Excessive amounts of a related compound, acetyl-CoA, have been found to be harmful in this context, and the enzyme ACOT12 breaks apart acetyl-CoA, leading to better outcomes in a mouse model [3]. Other components of fatty acid metabolism have also been linked to osteoarthritis progression [4].
Sterol regulatory element-binding transcription factor1 (SREBP1) is a key factor in the generation of these fatty acids, and the researchers note that its expression is linked to disc degeneration. They also point to research showing that the mouse gene Sesn2 inhibits the production of these fatty acids; mice without this gene swiftly accumulate deadly fat deposits in their livers [5]. As indirect upregulation of this gene has been associated with better knee cartilage and healthier cartilage-generating chondrocytes [6], and its overexpression ameliorates spinal arthritis in rats [7]. Therefore, these researchers sought to determine the link between SESN2, fatty acid synthesis, and outcomes in knee osteoarthritis.
SESN2 is broadly beneficial against arthritis in mice
The researchers’ first experiment involved human donor cartilage divided between healthy and damaged samples. As expected, the damaged samples had less SESN2 than the healthy samples, along with more expression of destructive factors and less expression of constructive ones; less SESN2 was found to be directly correlated to more lipid deposits and more of the metalloproteinase MMP3, which degrades cartilage. Other testing found that there was also less SESN2 in osteoarthritic model mice than healthy ones, and older wild-type mice were found to have less SESN2 than younger ones.
A follow-up experiment involved using RNA to directly silence Sesn2 in murine chondrocytes, and the results were similar to the damaged human samples, with increases in metalloproteinases and more destructive factors along with a corresponding decrease in constructive ones. Crucial genes, including sirtuins, were downregulated by this silencing as well. These Sesn2-silenced chondrocytes also had significantly increased lipid accumulation along with increased markers of cellular senescence, including p16, p21, and p53.
On the other hand, upregulating Sesn2 improved the balance between destruction and construction in chondrocytes stimulated with the inflammatory factor IL-1β. Lipid accumulation in the affected cells was significantly diminished, and senescence biomarkers were reduced.
Establishing the link
These results were found to indeed be due to SREBP1, which the researchers confirmed to be inversely correlated with Sesn2 expression. Directly activating this factor through ammonium chloride resulted in very similar effects as downregulating Sesn2, increasing metalloproteinases along with the enzymes that produce fatty acids. A mouse experiment demonstrated this relationship; mice that had upregulated Sesn2 but also had SREBP1 forcibly increased suffered from the same problems as mice that had downregulated Sesn2.
However, upregulating Sesn2 without directly affecting SREBP1 led to across-the-board benefits against osteoarthritis in wild-type mice that had experienced a debilitating knee surgery. The affected mice had less signs of knee osteoarthritis, significant decreases in fatty acids, reductions in swelling, reduced oversensitivity to pain, and more endurance.
The researchers believe that targeting SESN2, therefore, is a valid and viable potential therapy for treating osteoarthritis in people. However, this study did not involve drug discovery, and a mechanism for accurately targeting SESN2 or SREBP1 has not yet been determined. Substantial further work must be done in order to determine how this approach could potentially be used in the clinic.
Literature
[1] Reyes, C., Leyland, K. M., Peat, G., Cooper, C., Arden, N. K., & Prieto‐Alhambra, D. (2016). Association between overweight and obesity and risk of clinically diagnosed knee, hip, and hand osteoarthritis: a population‐based cohort study. Arthritis & Rheumatology, 68(8), 1869-1875.
[2] Wu, C. L., Jain, D., McNeill, J. N., Little, D., Anderson, J. A., Huebner, J. L., … & Guilak, F. (2015). Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury. Annals of the rheumatic diseases, 74(11), 2076-2083.
[3] Park, S., Baek, I. J., Ryu, J. H., Chun, C. H., & Jin, E. J. (2022). PPARα− ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis. Nature communications, 13(1), 3.
[4] Jeon, Y. G., Kim, Y. Y., Lee, G., & Kim, J. B. (2023). Physiological and pathological roles of lipogenesis. Nature Metabolism, 5(5), 735-759.
[5] Fang, Z., Kim, H. G., Huang, M., Chowdhury, K., Li, M. O., Liangpunsakul, S., & Dong, X. C. (2021). Sestrin proteins protect against lipotoxicity-induced oxidative stress in the liver via suppression of C-Jun N-terminal kinases. Cellular and Molecular Gastroenterology and Hepatology, 12(3), 921-942.
[6] Wu, Y., Li, X., Meng, H., Wang, Y., Sheng, P., Dong, Y., … & Wang, X. (2024). Dietary fiber may benefit chondrocyte activity maintenance. Frontiers in Cellular and Infection Microbiology, 14, 1401963.
[7] Sun, J., Song, F. H., Wu, J. Y., Zhang, L. Q., Li, D. Y., Gao, S. J., … & Mei, W. (2022). Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation. Brain, behavior, and immunity, 102, 53-70.
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