TSG-6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF-κB signaling pathway

Abstract

Inflammation has been correlated with intervertebral disc degeneration (IDD). Recent evidence suggests that TNF-α-stimulated gene 6 protein (TSG-6) secreted by bone marrow mesenchymal stem cells (BMSCs) displays a remarkable ability to inhibit inflammatory processes in a variety of diseases. However, it is unknown whether BMSCs exert their therapeutic effect against IDD by secreting TSG-6. Here we investigated the effects of BMSCs and TSG-6 on IDD and explored the possible underlying mechanisms in vitro and in vivo. We found that BMSCs and TSG-6 reduced the expression of MMP-3 and MMP-13, and increased the expression of collagen II and aggrecan in the IL-1β-treated nucleus pulposus cells (NPCs), but the protective effects of BMSCs and TSG-6 were attenuated when TSG-6 expression was silenced. We also found that the activation of the TLR2/NF-κB pathway was inhibited by BMSCs and TSG-6. The levels of IL-6 and TNF-α in the degenerated NPCs were reduced and the proliferation of IL-1β-treated NPCs was increased in the presence of BMSCs and TSG-6. Furthermore, in vivo experiments showed that BMSCs and TSG-6 restored the MRI T2-weighted signal intensity and increased collagen II and aggrecan expression in the degenerated nucleus pulposus (NP) tissues. Finally, our results showed that BMSCs and TSG-6 downregulated the TLR2/NF-κB signaling and reduced the expression of MMPs and inflammatory cytokines in the degenerated NP tissues. The present study is the first to demonstrate the involvement of TLR2/NF-κB pathway in the potential anti-IDD therapeutic effect of TSG-6, and the results provide new insight into the beneficial effect of BMSCs in the treatment of IDD.

Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia

“…Previous studies have shown that BMSCs can secrete TSG-6 to modulate the inflammatory microenvironment partly by inhibiting the activation of the TLR2/NF-κB signaling pathway [40,41]. Recently, we also proved that TSG-6 secreted by BMSCs can delay or even prevent intervertebral disc degeneration partly by suppressing the activation of the TLR2/MyD88/NF-κB signaling pathway in nucleus pulposus cells [27]. However, whether TSG-6 secreted by BMSCs exerts an anti-nociceptive effect in neuropathic pain by directly inhibiting the activation of the TLR2/ MyD88/NF-κB signaling pathway in spinal dorsal horn microglia remains unclear.…”

“…Isolation, culture, and identification of BMSCs SD rat primary BMSCs were prepared as previously described [27]. Briefly, primary BMSCs were obtained from the bone marrow of the tibias and femurs of 4-week-old male SD rats under aseptic conditions.…”

“…Previous studies have demonstrated that the antiinflammatory protein TSG-6 secreted by BMSCs can inhibit the activation of the TLR2/MyD88/NF-κB signaling pathway [27,40]. In addition, it has been proven that TLR2 plays a key role in nerve injury-induced spinal cord glial cell activation and is necessary for the development of neuropathic pain [23].…”

“…Previous studies have found that TLR2 is widely expressed in the CNS and contributes to the nerve injury-induced spinal cord glial cell activation and is necessary for the development of neuropathic pain [23][24][25][26]. The myeloid differentiation factor-88 adaptor protein (MyD88) is involved in TLR2 signaling and leads to NF-κB activation, which results in the expression of NF-κB-targeted genes, such as TNF-α and IL-1β [27].…”

Inhibitory effect of the TSG-6 on the BMP-4/Smad signaling pathway and odonto/osteogenic differentiation of dental pulp stem cells

“…It can reverse liver fibrosis and ameliorate liver damage in mice. Furthermore, TSG-6 plays a role in the treatment of autoimmune diseases (22,23).…”