Rebamipide Attenuates Mandibular Condylar Degeneration in a Murine Model of TMJ-OA by Mediating a Chondroprotective Effect and by Downregulating RANKL-Mediated Osteoclastogenesis

Authors

Takashi Izawa , Hiroki Mori, Tekehiro Shinohara, Akiko Mino-Oka, Islamy Rahma Hutami, Akihiko Iwasa, Eiji Tanaka

Abstract

Abstractemporomandibular 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.

Link to Article

http://dx.doi.org/10.1371/journal.pone.0154107

Osteoclast Deficiency Contributes to Temporomandibular Joint Ankylosed Bone Mass Formation

Authors

L.H. He, E. Xiao, D.H. Duan, Y.H. Gan, Y. Zhang

Abstract

Ankylosed bone mass in temporomandibular joint ankylosis (TMJA) is an important factor affecting mouth-opening limitation. However, the mechanism underlying the occurrence of ankylosed bone mass remains unknown. Research has shown that osteoblasts and osteoclasts maintain balance in bone remodeling. Thus, we hypothesized that aberrant osteoclastogenesis and osteogenesis may be involved in the occurrence of ankylosed bone mass in TMJA. In this study, we characterized the osteogenesis of bone marrow stem cells and the osteoclastogenesis of myelomonocyte in clinical specimens of TMJA and normal controls. Results showed that, compared with control bone marrow stem cells, TMJA bone marrow stem cells had lower proliferative and osteogenic capacities. The number of osteoclasts in the ankylosed bone mass group dramatically decreased, and myelomonocyte osteoclastogenic potential was impaired. The RANKL/OPG ratio of the ankylosed bone mass group was lower than that of the control group. Thus, our study suggests that osteoclast deficiency may be an important factor affecting bone mass ankylosis.