Exogenous Klotho ameliorates extracellular matrix degradation and angiogenesis in intervertebral disc degeneration via inhibition of the Rac1/ PAK1/MMP-2 signaling axis

Intervertebral disc degeneration (IDD) is highly ubiquitous in the aged population and is an essential factor for low back pain and spinal disability. Because of the association between IDD and senescence, we investigated the ability of the anti-aging drug Klotho to inhibit age-dependent advancement of nucleus pulposus cell (NPC) degeneration. The results indicated that 400 pM exogenous Klotho significantly ameliorated extracellular matrix degradation and angiogenesis. Moreover, we demonstrated that the suppression of angiogenesis and extracellular matrix catabolism was related to inhibition of the Ras-related C3 botulinum toxin substrate 1 (Rac1)/PAK1 axis and matrix metalloproteinase 2 protein expression by exogenous Klotho cotreatment with a Rac1 inhibitor, gene overexpression in NPCs, and stimulation of human umbilical vein endothelial cells with conditioned medium from NPCs. The treatment also preserved the NPC phenotype, viability, and matrix content. In conclusion, these results suggest that the new anti-aging drug Klotho is a potential treatment strategy to mitigate IDD, and thus, provides an innovative understanding of the molecular mechanism of IDD.Data availability: All data supporting the findings of this study are available from the corresponding authors upon reasonable request.