Icariin protects vertebral endplate chondrocytes against apoptosis and degeneration via activating Nrf-2/HO-1 pathway

Abstract

Cartilage endplate (CEP) plays important roles in the onset and progression of intervertebral disc degeneration (IVDD). Icariin (ICA) is the major active ingredient of Herba Epimedii and has various biological activities such as anti-inflammatory and antioxidant, which is used to treat many degenerative diseases. However, the effects and mechanism of ICA on endplate chondrocytes are still unclear. Herein, we studied the effects of ICA on CEP degeneration and elucidated the underlying mechanisms. Endplate chondrocytes were isolated, and TNF-α and TBHP were applied to mimic an IVDD pathological environment. Also, an IVDD mice model was established by transection of bilateral facet joints to investigate the protective effect of ICA in vivo. We found that ICA treatment inhibited the chondrocytes apoptosis and the decrease of extracellular matrix production in a dose-dependent manner. Our in vivo experiments demonstrated that ICA could ameliorate IVDD development and CEP calcification. We also found that the ICA-activated Nrf-2/HO-1 pathway thus promoted the Parkin-mediated mitophagy process and inhibited chondrocytes ferroptosis, thus alleviated redox imbalance and mitochondrial dysfunction and eventually improved cell survival. Knockdown of Nrf-2 using siRNA reversed the protective effect of ICA on endplate chondrocytes apoptosis and degeneration. In conclusion, our study demonstrated that ICA could protect against CEP degeneration and calcification under IVDD pathological conditions, the associated mechanism may be related to Nrf-2/HO-1-mediated mitophagy activation and ferroptosis inhibition. Our results suggest that ICA may be a potential effective medicine for IVDD prevention and treatment.

Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment

“…Tang et al 109 showed that Nrf2 knockdown reduced autophagy‐related protein (ATG) expression, which exacerbated H 2 O 2 ‐induced IVD degeneration. Furthermore, icariin (ICA) inhibited H 2 O 2 ‐induced mitochondrial dysfunction, oxidative stress and apoptosis in CEP cells by activating Nrf2/HO‐1 signalling axis, while Nrf2 knockdown reversed the protective effects of ICA 110,111 . In conclusion, activation of the keap1‐Nrf2‐ARE signalling pathway can inhibit oxidative stress and apoptosis and activate autophagy in IVD cells to delay IDD.…”

Natural products can modulate inflammation in intervertebral disc degeneration

“…In another study, these authors found that icariin could effectively resist oxidative stress damage caused by hydrogen peroxide and maintain mitochondrial homeostasis ( Hua et al, 2020 ). Shao et al (2022) further found that icariin could prevent the degeneration and calcification of CEP by inhibiting cell apoptosis and ferroptosis. Baicalein, a flavonoid with an anti-inflammatory effect, is found in abundance in Scutellaria baicalensis ( Tuli et al, 2020 ).…”

PTEN inhibitor VO-OHpic protects endplate chondrocytes against apoptosis and calcification via activating Nrf-2 signaling pathway

“…Twenty-one eight weeks old male C57BL/6 mice were randomly divided into 3 groups: control group, IDD group and IDD+VO-OHpic group. The IDD model, established by surgically-induced instability, had previously been published [ 34 ]. Briefly, the L4/5 bilateral facet joints, supra- and interspinous ligaments were transected surgically by microscissors using a surgical microscope to induce supra-physiologic movement.…”