Inhibiting tumor necrosis factor‐alpha at time of induced intervertebral disc injury limits long‐term pain and degeneration in a rat model

Abstract

Background: Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor-alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear. Purpose: Treatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro-inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro-inflammatory cytokine expression. Methods: Lumbar IVDs were punctured anteriorly and injected with TNFα, anti-TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6-weeks post-surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin-1 beta (IL-1β) expressions were assayed. Results: Intradiscal TNFα injection increased pain and IVD degeneration whereas anti-TNFα alleviated pain to sham level. Multivariate step-wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL-1β. Discussion: The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes.

Preclinical ex-vivo Testing of Anti-inflammatory Drugs in a Bovine Intervertebral Degenerative Disc Model

“…As far as we know, this is the first study evaluating antiinflammatory effects of Etanercept and Tofacitinib within a proinflammatory and degenerative microenvironment of a whole organ IVD culture model. Both, Etanercept and Tofacitinib partially prevented the upregulation of proinflammatory cytokines in IVDs cultured under IDD-like conditions which supports outcome of previous in vitro studies on TNF-α inhibition (Likhitpanichkul et al, 2015;Walter et al, 2015b;Evashwick-Rogler et al, 2018). Moreover, our data confirms the concept of recent work investigating a potential involvement of the IL-6/JAK/STAT3 pathway in IDD (Suzuki et al, 2017).…”

“…Recent studies indicated that the presence of TNF-α causes an upregulation of major catabolic enzymes involving Matrix-Metalloproteinases (MMPs) and A Disintegrin and Metalloprotease with Thrombospondin Motifs (ADAMTS), contributing to advanced structural decay in IDD (Purmessur et al, 2013;Tian et al, 2013;Baptista et al, 2020;Zhou et al, 2020). Moreover, TNF-α is associated with the development of discogenic pain by upregulating pain transmitter substance P (SP) and by attracting nerve ingrowth into the outer annulus fibrosus (Freemont et al, 1997(Freemont et al, , 2002Olmarker and Larsson, 1998;Igarashi et al, 2000;Risbud and Shapiro, 2014;Evashwick-Rogler et al, 2018).…”

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments

“…At this time point, it seems that hydration of the disc by itself (upon vehicle injection) also contributes to reducing hernia volume, although not statistically significantly. This was unexpected, but an effect of vehicle intradiscal injection has been reported before; for example, phosphate-buffered saline (PBS) and TNF-α intradiscal injections induced similar IVD degeneration [22]. Nonetheless, despite Df's short biologic half-life, it can be envisaged for local control of acute inflammation.…”

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

“…16 Solely upregulation of wnt/β-catenin signaling caused no proliferation in rat-derived NP cells however, cell viability was determined to decrease with 50%. 32 Moreover, wnt/β-catenin signaling was demonstrated to regulate tumor necrosis factor (TNF)-α, 47 linking it to IVD degeneration, 50,51 suggesting once more that the balance of canonical and noncanonical signaling is crucial for the outcome of wnt3a treatment. Interestingly, upregulation of the PKC pathway, of the noncanonical signaling pathway, induced cell proliferation in rat NP cells.…”