α-ketoglutaric acid ameliorates intervertebral disc degeneration by blocking the IL-6/JAK2/STAT3 pathway

Intervertebral disc degeneration (IVDD) is the major cause of low back pain. Alpha-ketoglutaric acid (α-KG), an important intermediate in energy metabolism, has various functions, including epigenetic regulation, maintenance of redox homeostasis, and Anti-aging, but whether it can ameliorate IVDD has not been reported. Here, we examined the impacts of long-term administration of a-KG on aging-associated IVDD in adult rats. In vivo and in vitro experiments showed that α-KG supplementation effectively ameliorated IVDD in rats and the senescence of nucleus pulposus cells (NPCs). α-KG supplementation significantly attenuated senescence, Apoptosis and MMP-13 protein expression, and it increased the synthesis of aggrecan and collagen II in IL-1β-treated NPCs. In addition, α-KG supplementation reduced the levels of IL-6, phosphorylated JAK2 and STAT3, and the nuclear translocation of p-STAT3 in IL-1β-induced degenerating NPCs. The effects of α-KG were enhanced by AG490 in NPCs. The underlying mechanism may involve the inhibition of JAK2/STAT3 phosphorylation and the reduction of IL-6 expression. Our findings may help in the development of new therapeutic strategies for IVDD.

IL-6/JAK/STAT3 pathway; alpha-ketoglutaric acid; intervertebral disc degeneration; senescence.