Toll-like receptor adaptor signaling molecule MyD88 on intervertebral disk homeostasis: In vitro, ex vivo studies

Abstract

MyD88 is an adapter protein that links toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs) with downstream signaling molecules. The MyD88 has been found to be an essential mediator in the development of osteoarthritis in articular cartilage. However, the role of the MyD88 pathway has yet to be elucidated in the intervertebral disk (IVD). Using in vitro techniques, we analyzed the effect of MyD88 pathway-specific inhibition on the potent inflammatory and catabolic mediator LPS and IL-1 in bovine and human nucleus pulposus (NP) cells by assessing matrix-degrading enzyme expression, including matrix metalloproteases (MMPs) and a disintegrin-like and metalloprotease with thrombospondin motifs (ADAMTS family). We also analyzed inhibition of MyD88 in the regulation of inducible nitric oxide synthase and TLR-2. Finally, we used an ex vivo organ culture model to assess the effects of MyD88 inhibitor (MyD88i) on catabolic factor-induced disk degeneration in mice lumbar disks. In bovine NP cells, MyD88i potently antagonizes LPS- or IL-1-mediated induction of cartilage-degrading enzyme production, including MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5. MyD88i also attenuates the LPS- or IL-1-mediated induction of iNOS and TLR-2 gene expression. Our ex vivo findings reveal inhibition of MyD88 via counteraction of IL-1-mediated proteoglycan depletion. The findings from this study demonstrate the potent anti-inflammatory and anti-catabolic effects of inhibition of MyD88 pathway inhibition on IVD homeostasis, suggesting a potential therapeutic benefit of a MyD88i in degenerative disk disease in the future.

Tanshinone IIA represses inflammatory response and reduces radiculopathic pain by inhibiting IRAK-1 and NF-κB/p38/JNK signaling

“…Inflammatory processes are regulated by TLRs, which are primarily expressed on the immune cells as a first line of host defense. Interestingly, TLRs are also expressed in IVD cells [39], which confer the clinical significance of inhibiting IVD inflammation.…”

miR‑148a inhibits pro‑inflammatory cytokines released by intervertebral disc cells by regulating the p38/MAPK pathway

“…One of the major features of IDD is the loss of proteoglycan (PG) content from IVDs. Lipopolysaccharide (LPS), a strong promoter of inflammation, can reduce PG content and cause the occurrence of IDD (9,10). Furthermore, pro-inflammatory factors such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α also serve critical functions in IDD.…”

Role of miR‑589‑3p in human lumbar disc degeneration and its potential mechanism

“…One of the major features of IDD is decrease of the proteoglycan (PG) content of IVDs (23). LPS, an admitted strong promoter of inflammation, can reduce the PG content, thus leading to IDD (24,25). Thus, in the present study, we used LPS to establish the IDD cell model for further study of miR-589-3p, and we found miR-589-3p was upregulated in human NP cells by LPS stimulated.…”