Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF-κB Pathway

Abstract

Antiaging protein Klotho exhibits impressive properties of anti-inflammation, however is declined early after intervertebral disc injury, making Klotho restoration an attractive strategy of treating intervertebral disc inflammatory disorders. Here, we have found that Klotho is enriched in nucleus pulposus (NP) cells and Klotho overexpression attenuates H2O2-induced acute inflammation essentially via suppressing Toll-like receptor 4 (TLR4). The proinflammatory NF-κB signaling and cytokine expressions paralleled with Klotho repression and TLR4 elevation in both NP cells (H2O2 treatment) and rat intervertebral disc (needle puncture treatment). Overexpression of TLR4 downregulated expression of Klotho, whereas interfering TLR4 expression diminished the inhibitory effects of H2O2 on Klotho in NP cells. Consistently, Klotho knockdown by RNA interferences largely diminished the anti-inflammatory and intervertebral disc protective effects in an Intervertebral Disc Degeneration (IDD) model. Thus, our study indicates that TLR4-NF-κB signaling and Klotho form a negative-feedback loop in NP cells. Also, we demonstrate that the expression of Klotho is regulated by the balance between upregulation and downregulation of TLR4-NF-κB signaling.

Lumbar Spine Abnormalities in Patients With Obstructive Sleep Apnoea

“…We have reported low levels of klotho in OSA which were associated with markers of overnight hypoxaemia [24]. In line with this, hypoxaemia [11] and oxidative stress [3] lead to decreased klotho expression in nucleus pulposus cells. Klotho attenuates in ammation at the same site [3] and it is hypothesised that lower klotho levels contribute to disc degeneration [3].…”

“…In line with this, hypoxaemia [11] and oxidative stress [3] lead to decreased klotho expression in nucleus pulposus cells. Klotho attenuates in ammation at the same site [3] and it is hypothesised that lower klotho levels contribute to disc degeneration [3]. In line with this, klotho gene polymorphisms were associated with lumbar spondylosis [22].…”

“…A potential molecule which is involved in the pathomechanism of both diseases is the klotho protein [3,24]. This protein is synthesised predominantly in the kidneys, but other organs, such as parathyroid gland, ovary, testis and placenta also express the klotho gene [16].…”

“…Most importantly, intermittent hypoxia may lead to oxidative stress and in ammation in the lumbar discs which could contribute to spinal disc degeneration [9]. A potential molecule which could be a link between OSA and discopathy is the anti-in ammatory klotho protein, which levels were found decreased both in plasma samples of patients with OSA [24] and in the nucleus pulposus specimens in disc degeneration [3].…”

Genetic Therapy for Intervertebral Disc Degeneration

“…In 2020, Bi et al [ 64 ] attenuated H₂O₂ induced acute inflammation by overexpressing the Klotho gene using RNAi using the IVDD rat model and inhibiting Toll-like receptor 4 (TLR4). As a result, Klotho inhibition and elevated TLR4 levels showed pro-inflammatory nuclear factor kappa B (NF-κB) signaling and cytokine expression in NP cells of all animal groups.…”