Temporomandibular joint osteoarthritis (TMJOA) is a common degenerative joint disease without effective intervention strategies. Previous research implied that alpha-kinase 1 (ALPK1) is involved in the inflammatory responses of gout, a chronic arthritis. Herein, we found the main distribution of ALPK1 in a proliferative layer of condylar cartilage and marrow cavity of subchondral bone, as well as a lining layer of synovial tissues in human temporomandibular joint. Moreover, the expression of ALPK1 was augmented in degraded condylar cartilage of monosodium iodoacetate (MIA)–induced TMJOA mice. After MIA induction, ALPK1 knockout mice exhibited attenuated damage of cartilage and subchondral bone, as well as synovitis, as compared with wide type mice. In contrast, intra-articular administration of recombinant human ALPK1 aggravated the pathology of MIA-induced TMJOA. Furthermore, ex vivo study demonstrated that ALPK1 exacerbated chondrocyte catabolism by upregulating matrix metalloproteinase 13 and cyclooxygenase 2 by activating NF-κB (nuclear factor–kappaB) signaling and suppressed anabolism by downregulating aggrecan by inhibiting ERK1/2 (extracellular signal–regulated kinase 1/2) in articular chondrocytes. Taken together, ALPK1 exacerbates the degradation of condylar cartilage during TMJOA through the NF-κB and ERK1/2 signaling pathway. This study provides a new insight regarding the role of ALPK1 during TMJOA pathology.

Temporomandibular joint osteoarthritis (TMJOA) is one of the most common diseases causing chronic pain in the oral and maxillofacial region. So far, there are few ways to relieve the pain of TMJOA. Melatonin (MT) has a good analgesic effect in many diseases, including fibromyalgia, neuropathic pain, chronic headache, and burn pain, with very low acute toxicity and side effects. This study was to investigate the role and mechanism of MT in TMJOA chronic pain. In rats TMJOA chronic pain occurred at day 14 after an intra–temporomandibular joint injection of monosodium iodoacetate, which we previously reported. The enzyme-linked immunosorbent assay results showed that MT levels were higher in the synovial fluid from patients and rats with TMJOA as compared with those from control. Fluorescent retrograde tracing (Dil) identified that upregulation of MT type 2 receptor (MT2R) in trigeminal ganglion (TG) neurons innervating rat temporomandibular joints was accompanied by TMJOA chronic pain. Nociceptive behavior as assessed by von Frey and the Rat Grimace Scale demonstrated that exogenous administration of MT relieved chronic pain in TMJOA rats, whereas blocking MT2R with 4P-PDOT reversed the analgesic effect of MT. Immunofluorescence analysis also confirmed that MT inhibited CGRP and IB4 expression of TG neurons, and this inhibition was reversed by administering the MT2R antagonist in TMJOA rats. By using Fluo-3 AM-based calcium imaging in vitro, MT elicited calcium transients in Dil+ TG neurons, which were significantly abolished by 4P-PDOT. Collectively, this study suggested that MT relieves the TMJOA chronic pain of rats through downregulation of sensitized CGRP+ and IB4+ neurons in TG via MT2R. This will be helpful for health care professionals utilizing MT as an option against TMJOA chronic pain.