Xing Long

The mandibular condyle is covered by fibrocartilage, and its degeneration, termed temporomandibular joint osteoarthritis (TMJOA), currently lacks effective disease‐modifying therapies. In this study, we uncover a previously unrecognized mechanism by which the extracellular matrix protein TGFBI (TGF‐β‐induced) sustains condylar fibrocartilage homeostasis by restraining protein O‐GlcNAcylation. We demonstrate that TGFBI is predominantly expressed in the condylar perichondrium and is markedly downregulated in both TMJOA patients and corresponding mouse models. Genetic ablation of Tgfbi delays postnatal skeletal development, promotes chondrocyte hypertrophy, and accelerates fibrocartilage degeneration. Mechanistically, TGFBI functions as a negative regulator of O‐GlcNAcylation in condylar perichondrial cells (cPCs), thereby suppressing both the transcriptional activation and protein stability of the matrix protease ADAMTS16. Notably, ex vivo studies identify Ser1170 of ADAMTS16 as a critical O‐GlcNAcylation site that directly governs its protein turnover. By inhibiting O‐GlcNAcylation at this residue, TGFBI prevents condylar chondrocyte hypertrophy, senescence, and extracellular matrix degradation. Collectively, our findings establish the TGFBI–O‐GlcNAcylation–ADAMTS16 axis as a vital driver of condylar fibrocartilage degeneration and highlight a promising metabolic target for TMJOA therapy.

Alpha‐kinase 1 (Alpk1) is identified as a novel pattern recognition receptor with immunomodulatory functions in inflammatory responses. This study investigates the previously unexplored role of Alpk1 in synovial angiogenesis and chondrocyte ferroptosis during osteoarthritis (OA) progression, a degenerative joint disorder currently lacking curative therapies. Utilizing a collagenase‐induced OA (CIOA) murine model, we employed Alpk1 knockout mice and intra‐articular administration of recombinant human Alpk1 (rhAlpk1) to elucidate its mechanistic involvement. Our findings demonstrate significant upregulation of Alpk1 in degenerated cartilage and inflamed synovium, with expression levels positively correlating with the severity of cartilage degradation. Intra‐articular rhAlpk1 administration exacerbated synovial angiogenesis and chondrocyte oxidative stress in CIOA mice, whereas Alpk1 deficiency attenuated these pathological processes. In vitro analyses revealed that von Willebrand factor (VWF) mediated rhAlpk1‐induced angiogenesis in human umbilical vein endothelial cells, while glutathione peroxidase 4 (GPX4) exerted inhibitory effects on Alpk1‐mediated chondrocyte ferroptosis. Subsequent in vivo validation confirmed that Alpk1 promotes angiogenesis through VWF signaling activation and exacerbates oxidative stress‐induced chondrocyte ferroptosis via GPX4 pathway suppression in the CIOA model. This study establishes that Alpk1 deficiency confers protection against inflammatory OA by dual mechanisms: suppressing synovial angiogenesis through modulation of VWF signaling, and mitigating chondrocyte ferroptosis via GPX4 signaling pathway regulation. These findings provide novel mechanistic insights into OA pathogenesis and highlight Alpk1 as a potential therapeutic target for OA intervention.

Objectives This study aimed to analyze the positional characteristics of the temporomandibular joint (TMJ) disc in patients with anterior disc displacement without reduction (ADDWoR) using magnetic resonance imaging (MRI). Materials and Methods 2,827 MRI images from 2,168 ADDWoR patients were collected and categorized into two groups: without limited opening (WoLO) group and with limited opening (WLO) group. The position of TMJ disc and their distribution characteristics in these two groups were analyzed from the oblique sagittal planes of MRI. Results The disc positions were classified into 11 types based on oblique sagittal MRI images during maximum mouth opening. Anterior displacement was the most common in both groups, with 39.65% in WoLO and 41.96% in WLO. Anteroinferior displacement and anteroinferior displacement in the lateral part were also prevalent, particularly in the WLO group. While the MRI imaging features of superior displacement did not appear in the WLO group, due to mouth opening limitation. The effect of masticatory muscles and condylar excursion during mouth opening play a crucial role in the displacement of TMJ disc. Conclusions ADDWoR patients of WoLO group primarily manifest disc anterior displacement, anteroinferior in the lateral part, and anteroinferior displacement. ADDWoR patients of WLO group are more likely to exhibit disc anterior displacement and anteroinferior displacement, without the manifestation of superior displacement. Clinical Relevance The position of the anterior displaced disc can guide treatment strategies, conservative treatment alleviating restricted mouth opening for anteroinferior displacement patients, or controlling excessive mouth opening to relieve ligamentous laxity for anterosuperior displacement patients.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that plays a vital role in innate immune responses. This study aims to investigate the effect of TREM2 on synovial barrier homeostasis and synovitis during temporomandibular joint osteoarthritis (TMJOA). The expression level of TREM2 is decreased in the synovium of both patients with TMJOA and a mouse model of TMJOA, accompanied by synovial barrier breakdown. TREM2 overexpression inhibits the macrophage inflammatory response ex vivo and relieves synovial inflammation, cartilage degeneration, and synovial barrier destruction in monosodium iodoacetate–induced TMJOA mice. RNA-seq analysis reveals that Siglec1 serves as a downstream signal that is downregulated after TREM2 activation. Further in vivo and in vitro experiments demonstrate that rhSiglec1 treatment promotes the synthesis and release of inflammatory cytokines, such as interleukin-6 and RANTES, in macrophages and reverses the alleviation effect of TREM2 activation on TMJOA synovial barrier disorders, synovial inflammation, cartilage degradation, and bone destruction. Overall, this study verifies that TREM2 activation alleviates TMJOA pathology by maintaining synovial barrier homeostasis and inhibiting synovial inflammation. These findings provide new insight into the mechanism of TREM2 in the pathogenesis of TMJOA.

M1 macrophage polarization and synovitis play an important role in the pathogenesis of temporomandibular joint osteoarthritis (TMJOA). Reduced molecular weight of hyaluronic acid (HA) in synovial fluid of patients with TMJOA. In addition, high molecular weight hyaluronic acid (HMW‐HA) is often used clinically to treat TMJ inflammation. As a pattern recognition receptor of the cytoplasm, ALPK1 was found to be pro‐inflammatory in a variety of diseases. However, the relationship of ALPK1, HA and M1 macrophage polarization in TMJ synovitis remains unclear. We aimed to investigate the role of ALPK1 and HA in macrophage polarization and TMJ synovitis and the underlying mechanisms. The results demonstrated that ALPK1 was highly upregulated in the synovial macrophages in the inflamed TMJ synovium of patients. Low molecular weight hyaluronic acid (LMW‐HA) promoted the expression of ALPK1 and M1 macrophage‐associated genes. Besides, rhALPK1 promoted the expression of M1 macrophage‐associated factors and the nuclear translocation of PKM2. Furthermore, ALPK1 knockout mice exhibited limited infiltration of macrophages and decreased expression levels of M1 macrophage‐associated genes in CFA‐induced TMJ synovitis. While HMW‐HA inhibited the expression of ALPK1 and M1 macrophage polarization. Our results elucidated that ALPK1 promoted TMJ synovitis by promoting nuclear PKM2‐mediated M1 macrophage polarization, whereas HMW‐HA inhibited the expression of ALPK1 as well as M1 macrophage polarization.

Background: Phenotype alterations of nociceptive neurons have been shown to be a key step in the pathogenesis of many pain‐related diseases. However, it is unclear if the characteristic changes of temporomandibular joint (TMJ) primary afferent neurons are related to the pathogenesis of temporomandibular joint osteoarthritis (TMJOA) chronic pain. This study aimed to determine the morphological and neurochemical changes in trigeminal ganglion (TG) neurons innervating the TMJ in TMJOA chronic pain rats.Materials and Methods: Monosodium iodoacetate (MIA)‐induced TMJOA chronic pain rat model was established (n = 6), and saline was injected in rats of the control group (n = 6). TMJ primary afferent neurons were labeled with retrograde tracing (Dil). The spatial distribution and the expression of calcitonin gene‐related peptide (CGRP), isolectin B4 (IB4), and neurofilament 200 (NF200) of TMJ primary afferent neurons in TG were investigated using immunofluorescence. Intracellular calcium signaling was recorded by calcium imaging (n = 20).Results: TMJ primary afferent neurons were located only in the V3 region of the TG from both saline‐ and MIA‐injected rats. The number of TG neurons innervating the TMJ was increased in MIA‐injected rats. Elevated number and intracellular calcium concentration of small‐ and medium‐sized instead of large‐sized Dil+ TG neurons were found in MIA‐injected rats. The upregulated expression of CGRP and IB4, but not NF200, in TG neurons innervating the rat TMJs was accompanied by TMJOA chronic pain.Conclusion: This study suggests that sensitization of small‐ to medium‐sized Dil+ TG neurons and CGRP‐ and IB4‐positive Dil+ TG neurons might contribute to the development of TMJOA chronic pain in rats. This will provide valuable information for more efficient control of TMJOA chronic pain.