The PI3K/Akt pathway: a critical player in intervertebral disc degeneration

Abstract

Intervertebral disc degeneration (IDD) is thought to be the primary cause of low back pain, a severe public health problem worldwide. Current therapy for IDD aims to alleviate the symptoms and does not target the underlying pathological alternations within the disc. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway protects against IDD, which is attributed to increase of ECM content, prevention of cell apoptosis, facilitation of cell proliferation, induction or prevention of cell autophagy, alleviation of oxidative damage, and adaptation of hypoxic microenvironment. In the current review, we summarize recent progression on activation and negative regulation of the PI3K/Akt signaling pathway, and highlight its impact on IDD. Targeting this pathway could become an attractive therapeutic strategy for IDD in the near future.

Keywords: Akt; IDD; PI3K; PTEN; mTOR.

Figure 1. Schematic diagram of the PI3K/AKT pathway

PI3K is activated upon binding of an extracellular ligand to RTK, GPCR or Ras. Activated PI3K converts PIP2 to PIP3, which is able to be reversed by PTEN. PIP3 then recruits PDK1, which phosphorylates and partially activates Akt. The mTORC2 mediates the second phosphorylation to fully activate AKT. Subsequently, the formation of the TSC1/2 heterodimer is significantly decreased, which leads to a marked increase in Rheb-GTP content and mTORC1 activation. The mTORC1 induces S6K phosphorylation to release 4E-BP1, which stimulate protein synthesis and cell proliferation. Akt activation enhances cyclin D1 and CDK expression by inhibiting GSK3β and FoxO1, respectively. Both effects contribute to cell cycle progression. Activated Akt can also suppress apoptosis via regulating the expression of apoptosis-associated genes. Raptor, regulatory-associated protein of mTOR; GβL, mammalian LST8/G-protein β-subunit like protein; PRAS40, proline-rich Akt substrate 40; Deptor, DEP domain containing mTOR-interacting protein; mSIN1, mammalian stress-activated protein kinase interacting protein 1.

Figure 2. Illustration of PI3K/Akt-mediated protection against IDD and the underlying mechanisms

Activation of this pathway increases ECM content via downregulating MMP-3 and MMP-13 expression and upregulating Sox9 expression, inhibits apoptosis by activating mTOR and attenuating caspase-3 activity, and promotes cell proliferation by upregulating cyclin D1 expression. This pathway can also suppress autophagy by activating mTOR, alleviate oxidative injury via activating the Nrf2/HO-1 signaling and decreasing ROS levels, and enhance adaptation of hypoxic microenvironment by upregulating HIF-1α expression and inactivating GSK3β. All of these effects result in alleviation of disc degeneration.

Figure 3. Involvement of autophagy in PI3K/Akt-mediated protection against IDD

Autophagy is a successive process involving the formation of phagophores, autophagosomes and autolysosomes, and degradation of vesicle contents. Activating the PI3K/AKT pathway can antagonize or induce IVD cell autophagy, thereby leading to inhibition of disc degeneration.