TAP2, a peptide antagonist of Toll-like receptor 4, attenuates pain and cartilage degradation in a monoiodoacetate-induced arthritis rat model

Abstract

Because inflammation in osteoarthritis (OA) is related to the Toll-like receptor 4 (TLR4) signaling cascades, TLR4 is a reasonable target for developing therapeutics for OA. Thus, we investigated whether TAP2, a peptide antagonist of TLR4, reduces the monoiodoacetate (MIA)-induced arthritic pain and cartilage degradation in rats. TLR4 expression of human OA chondrocytes and synoviocytes and the knee joint tissue of MIA-induced arthritis were evaluated. MIA-induced arthritic model using Sprague–Dawley rats (6 week-old-male) were treated with TAP2, a TLR4 antagonist, and evaluated with behavioral test, immunohistochemistry, and quantitative PCR. TLR4 was highly expressed in the knee joints of patients with OA and the MIA-induced rat model. Further, a single intraarticular injection of TAP2 (25 nmol/rat) molecules targeting TLR4 on day 7 after MIA injection dramatically attenuated pain behavior for about 3 weeks and reduced cartilage loss in the knee joints and microglial activation in the spinal dorsal horns. Likewise, the mRNA levels of TNFα and IL-1β, reactive oxygen species, and the expression of MMP13 in the knee joints of TAP2-treated rats was significantly decreased by TAP2 treatment compared with the control. Moreover, interestingly, the duration of OA pain relief by TAP2 was much longer than that of chemical TLR4 antagonists, such as C34 and M62812. In conclusion, TAP2 could effectively attenuate MIA-induced arthritis in rats by blocking TLR4 and its successive inflammatory cytokines and MMP13. Therefore, TAP2 could be a prospective therapeutic to treat patients with OA.

TLR4 Antagonism Reduces Movement-Induced Nociception and ATF-3 Expression in Experimental Osteoarthritis

“… 59 In agreement, we observed no improvement in the histopathology of the joint of OA animals receiving the TLR4 antagonist, despite the reduction in nociception and in neuronal injury, which reinforces the possible distinct actions of the TLR4 pathway. This is in contrast with the study of Park et al 11 which showed a reduction of cartilage degradation upon TAP2 administration. However, since inflammatory events involving TLR4 are complex, the two antagonists might produce different effects in the downstream pathway.…”

“…Being the TLR4 responsible for their recognition and for the expression of costimulatory molecules on antigen presenting cells, 42 , 43 TLR4-A1 could be blocking this immune-mediated response, possibly by preventing the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway and the production of TNF-α and IL-1β at the joint, which will lead to a reduction in the excitability of primary afferent neurons and to a reduction of movement-related nociception. 44 Park et al 11 have also recently showed that intra-articular administration of TAP2, a peptide antagonist of TLR4, suppressed the expression of pro-inflammatory cytokines at the joint of OA animals and also reduced the secondary mechanical allodynia. ATF-3, an adaptive response gene induced by a variety of stress signals, 45 is not expressed in most healthy intact neurons, but its expression is induced following nerve injury, 46 being associated with neuroprotective and regenerative effects in the peripheral nervous system.…”

“… 9 , 10 TLR4 increased expression has also been observed in synoviocytes of OA synovium. 11 On the other hand, several Damage-Associated Molecular Patterns (DAMPs), generated by the injured tissues in OA, can activate TLR4. These include small degradation fragments of hyaluronic acid, fibronectin fragments, the calcium-binding proteins S100-A8 and S100-A9 and the high mobility group protein B1 (HMGB1).…”

Amitriptyline blocks innate immune responses mediated by toll‐like receptor 4 and IL‐1 receptor: Preclinical and clinical evidence in osteoarthritis and gout

“…The blockade of IL-1 receptor is used to treat rheumatoid arthritis (Mertens & Singh, 2009), gout (Pascart & Richette, 2017) and crystal-induced arthritis (Aouba et al, 2015). Although TLR4 has been proposed as a therapeutic target for osteoarthritis and other arthritides (H. Park et al, 2020), a viable TLR4 inhibitor has yet to be found.…”

“…The blockade of IL‐1 receptor is used to treat rheumatoid arthritis (Mertens & Singh, 2009 ), gout (Pascart & Richette, 2017 ) and crystal‐induced arthritis (Aouba et al, 2015 ). Although TLR4 has been proposed as a therapeutic target for osteoarthritis and other arthritides (H. Park et al, 2020 ), a viable TLR4 inhibitor has yet to be found. Considering this, we determined whether amitriptyline, a drug that binds to TLR4 in mouse microglial cells (Hutchinson et al, 2010 ), could be repurposed as a TLR4 blocking agent to inhibit articular innate immune responses.…”