Abstract
Temporomandibular joint osteoarthritis (TMJ-OA) is characterized by progressive degradation of cartilage and changes in subchondral bone. It is also one of the most serious subgroups of temporomandibular disorders. Rebamipide is a gastroprotective agent that is currently used for the treatment of gastritis and gastric ulcers. It scavenges reactive oxygen radicals and has exhibited anti-inflammatory potential. The aim of this study was to investigate the impact of rebamipide both in vivo and in vitro on the development of cartilage degeneration and osteoclast activity in an experimental murine model of TMJ-OA, and to explore its mode of action. Oral administration of rebamipide (0.6 mg/kg and 6 mg/kg) was initiated 24 h after TMJ-OA was induced, and was maintained daily for four weeks. Rebamipide treatment was found to attenuate cartilage degeneration, to reduce the number of apoptotic cells, and to decrease the expression levels of matrix metalloproteinase-13 (MMP-13) and inducible nitric oxide synthase (iNOS) in TMJ-OA cartilage in a dose-dependent manner. Rebamipide also suppressed the activation of transcription factors (e.g., NF-κB, NFATc1) and mitogen-activated protein kinases (MAPK) by receptor activator of nuclear factor kappa-B ligand (RANKL) to inhibit the differentiation of osteoclastic precursors, and disrupted the formation of actin rings in mature osteoclasts. Together, these results demonstrate the inhibitory effects of rebamipide on cartilage degradation in experimentally induced TMJ-OA. Furthermore, suppression of oxidative damage, restoration of extracellular matrix homeostasis of articular chondrocytes, and reduced subchondral bone loss as a result of blocked osteoclast activation suggest that rebamipide is a potential therapeutic strategy for TMJ-OA.
Highlights
Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative joint disease that is characterized by the death of chondrocytes, loss of cartilage extracellular matrix (ECM), and subchondral bone resorption in its early stages, followed by abnormal reparative bone turnover [1,2,3,4]
A mouse model of TMJ-OA was developed by subjecting the temporomandibular joints (TMJs) of C57BL/6 WT mice to mechanical stress with jaw-opening devices that were applied to the interincisal teeth to hold the mandible in the maximal opened position [26,27] (Fig 1)
The micro-CT results showed that the bone volume to trabecular volume ratio (BV/TV) ratio and the Tb.Th were reduced among different regions of the condylar subchondral bone in the TMJ-OA mice compared with the control mice (Fig 2A–2C)
Summary
Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative joint disease that is characterized by the death of chondrocytes, loss of cartilage extracellular matrix (ECM), and subchondral bone resorption in its early stages, followed by abnormal reparative bone turnover [1,2,3,4]. Osteoclast-mediated bone resorption and bone formation are tightly coupled. When the amount of bone resorption exceeds that of bone formation, subchondral bone loss often occurs [5]. Accumulating evidence has shown that cartilage-degrading proteinases and proinflammatory cytokines, such as matrix metalloproteinase-13 (MMP-13) and interleukin (IL)-1β, can promote catabolic processes that lead to the degeneration of cartilage and subchondral bone [7]. In diseases like OA and RA, deregulation of cellular proliferation and excess nitric oxide (NO) formation are hallmarks of cartilage degradation [11]. The apoptosis of chondrocytes appears to positively correlate with the severity of matrix depletion and destruction that are observed in osteoarthritic cartilage [15,16,17]
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