Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis

Abstract

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damageassociated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA.

Low‐frequency pulsed electromagnetic fields alleviate the condylar cartilage degeneration and synovitis at the early stage of temporomandibular joint osteoarthritis

“…[29][30][31][32] In this study, we observed that UAC induction significantly promoted the death of condylar chondrocytes at 3 weeks, mainly manifested as necroptosis, which was consistent with our previous study. 15 PEMF intervention, which effectively inhibited necroptosis of condylar chondrocytes, may serve as a protective mechanism of PEMF on TMJOA cartilage. Further studies and experiments are required to confirm the findings.…”

“…Thus, the early-stage TMJOA model was successfully established in 3 weeks and 6 weeks UAC group, which were consistent with our previous studies. 14,15,25 As a non-invasive physical therapy, PEMF is a promising method for the treatment of OA of extremity joints. Early studies had confirmed that PEMF could promote the synthesis of TGF-β1, inhibit the PEMF could inhibit the release of PGE2 and pro-inflammatory factor IL-6, IL-8, while promoting the secretion of anti-inflammatory factor IL-10.…”

“…In order to simulate the high incidence of TMJOA in young women, 36 6‐week‐old female SD rats provided by the Animal Center of Fourth Military Medical University, weighing 170–190 g, were utilized in the present study. In previous studies, we found that the condyle of rats in UAC group appeared early TMJOA‐like degeneration at 3 weeks and aggravated at 6 weeks 14,15 . Thus, according to the time point (3 weeks and 6 weeks), the rats were randomly divided into two groups, each of which was randomly divided into three subgroups: control group (CON), unilateral anterior crossbite group (UAC) and UAC + PEMF intervention group (U + P), with six rats in each subgroup.…”

“…In previous studies, we found that the condyle of rats in UAC group appeared early TMJOA-like degeneration at 3 weeks and aggravated at 6 weeks. 14,15 Thus, according to the time point (3 weeks and 6 weeks), the rats were randomly divided into two groups, each of which was randomly divided into three subgroups: control group (CON), unilateral anterior crossbite group (UAC) and UAC + PEMF intervention group (U + P), with six rats in each subgroup. During the study, all rats were raised in an aseptic environment and fed with sterilized food and distilled water.…”

Exploring Natural Compounds of Sungihwajungtang for TRPV1 Antagonistic and Anti-inflammatory Effect using in silico Method

“…As these proteins instigate the inflammation and modulate the inflammatory signaling pathways leading to TMD arthritis. [19][20] Whereas MAPK8, MAP4K4 and WNT7A contribute to the dedifferentiation of chondrocytes and prevent their regulation in response to an inflammatory insult to the cell. [21][22] On the other hand, the level of OLFML1 and MFAP4 is upregulated in TMD, 23 however, their role in TMD is still not understood.…”