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Abstract
Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose- and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells' apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD.
Highlights
Lower back pain is one of the most common musculoskeletal disorders that lead to low quality of life and high economic cost for the society
Nucleus pulposus cells shrunk in size, there was more vacuole formation and they floated in the medium under tert-butyl hydroperoxide (TBHP), whereas metformin could protect cells against apoptosis induced by TBHP (Figure 1d)
The real-time PCR results showed that TBHP treatment reduced mRNA levels of the major extracellular matrix (ECM) synthesis gene Col2a1, whereas metformin could attenuate the loss of Col2a1 expression (Figure 1h) (Po0.01)
Summary
Lower back pain is one of the most common musculoskeletal disorders that lead to low quality of life and high economic cost for the society. By 2013, up to 80% of the people suffered from low back pain in different stages of their lives.[1] Intervertebral disc degeneration (IDD) has been reported to be the major cause for low back pain.[2,3] until recently there are no efficacious drugs for IDD therapy. The intervertebral disc is composed of a gelatinous inner core, the nucleus pulposus, and tough outer rings, the annulus fibrosus. The gelatinous nucleus pulposus is the main functional composition of discs, which help them to confront diverse mechanical impact, whereas the tough annulus fibrosus is thought to form a circular ring structure to support the nucleus pulposus. It has been demonstrated recently that metformin could stimulate autophagy in various tissues including in brain,[16,17] kidney[18] and heart,[19] but not yet in nucleus pulposus. Methyladenine; siRNA, small interfering RNA; MRI, Magnetic resonance imagings; ELISA, enzyme-linked immunosorbent assay; ECM, major extracellular matrix; MMP-3, matrix metalloproteinase-3
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