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

A Comparison of Vascularity, Bone Mineral Density Distribution, and Histomorphometrics in an Isogenic Versus an Outbred Murine Model of Mandibular Distraction Osteogenesis

Authors

Edward G. Carey, Sagar S. Deshpande, Alexander R. Zheutlin, Noah S. Nelson, Alexis Donneys, Stephen Y. Kang, Kathleen K. Gallagher, Peter A. Felice, Catherine N. Tchanque-Fossuo, Steven R. Buchman

Abstract

Background
Vascularity, bone mineral density distribution, and histomorphometrics between the inbred, isogenic Lewis rat and the outbred, nonisogenic Sprague Dawley rat within mandibular distraction osteogenesis (MDO) must be compared in order for future researchers to compare results generated from these two animals. We hypothesize that little difference will be found between the two strains within these metrics.

Methods
The investigators implemented a comparative study between the Lewis and Sprague Dawley rat strains within MDO. The sample was composed of 17 male Lewis and 17 male Sprague Dawley rats, which underwent surgical external fixation and distraction. Rats’ hemimandibles were distracted to a total distance of 5.1 mm. After 28 days of consolidation, 9 rats from each group underwent bone mineral density distribution analysis. The remaining rats from each group were analyzed for vascular and histologic metrics. Descriptive and bivariate statistics were computed and the p-value was set at 0.05.

Results
We demonstrated successful mandibular distraction osteogenesis in all animals, with no significant difference found in histologic or bone mineral density distribution metrics. No significant differences were found in any of the vascular metrics, with the exception of vascular separation that was not normalized to mandibular volume (p = 0.048).

Conclusion
This study demonstrates that little dissimilarity exists between the isogenic Lewis and the outbred Sprague Dawley models of mandibular distraction osteogenesis. Given this, researchers may confidently compare gross results between the two strains while taking into consideration the very small differences between the models. For studies that require an isogenic strain, the Lewis rat is an apt surrogate for the Sprague Dawley strain.

Link to Article

http://dx.doi.org/10.1016/j.joms.2016.04.01

Sprouty2 regulates endochondral bone formation by modulation of RTK and BMP signaling

Authors

Adriane Joo, Roger Long, Zhiqiang Cheng, Courtney Alexander, Wenhan Chang, Ophir D. Klein

Abstract

Skeletal development is regulated by the coordinated activity of signaling molecules that are both produced locally by cartilage and bone cells and also circulate systemically. During embryonic development and postnatal bone remodeling, receptor tyrosine kinase (RTK) superfamily members play critical roles in the proliferation, survival, and differentiation of chondrocytes, osteoblasts, osteoclasts, and other bone cells. Recently, several molecules that regulate RTK signaling have been identified, including the four members of the Sprouty (Spry) family (Spry1–4). We report that Spry2 plays an important role in regulation of endochondral bone formation. Mice in which the Spry2 gene has been deleted have defective chondrogenesis and endochondral bone formation, with a postnatal decrease in skeletal size and trabecular bone mass. In these constitutive Spry2 mutants, both chondrocytes and osteoblasts undergo increased cell proliferation and impaired terminal differentiation. Tissue-specific Spry2 deletion by either osteoblast- (Col1-Cre) or chondrocyte- (Col2-Cre) specific drivers led to decreased relative bone mass, demonstrating the critical role of Spry2 in both cell types. Molecular analyses of signaling pathways in Spry2−/− mice revealed an unexpected upregulation of BMP signaling and decrease in RTK signaling. These results identify Spry2 as a critical regulator of endochondral bone formation that modulates signaling in both osteoblast and chondrocyte lineages.

Link to Article

http://dx.doi.org/10.1016/j.bone.2016.04.023

Peri-implant defect regeneration in the diabetic pig: a preclinical study

Authors

Cornelius von Wilmowsky, Karl Andreas Schlegel, Christoph Baran, Emeka Nkenke, Friedrich Wilhelm Neukam, Tobias Moest

Abstract

Objectives
The study aims to establish a peri-implant dehiscence-type bone defect in a diabetic animal model of human bone repair and to quantify the influence of diabetes on peri-implant bone regeneration.

Material and methods
Experimental diabetes was induced in three domestic pigs by streptozotocin. Three animals served as healthy controls. After 12 months four standardized peri-implant dehiscence bone defects were surgically created in the ramus mandibulae. The animals were sacrificed after 90 days. Samples were histologically analyzed to quantify new bone height (NBH), bone-to-implant-contact (BIC), area of newly formed bone (NFB), bone-density (BD), and bone mineralization (BM) in the prepared defect (- D) and in a local control region (-L).

Results
After 90 days, diabetic animals revealed a significantly lower BIC (p=0.037) and BD (p=0.041) in the defect area (-D). NBH and BM-D differences within the groups were not significant (p>0.05). Significant more NFB was measured in the healthy control group (p=0.046). In the region of local bone BIC-L was significant less in the diabetic group (p=0.028). In the local control region BD-L and BM-L was lower in the diabetic group compared to the healthy control animals (p>0.05).

Conclusion
Histological evidence indicates impaired peri-implant defect regeneration in a diabetic animal model.

Link to Article

http://dx.doi.org/10.1016/j.jcms.2016.04.002