Development of osteoarthritis-like changes in transgenic endothelin-1 over-expressed mice

Abstract

Introduction: Hypertension and type 2 diabetes mellitus are frequently encountered in knee osteoarthritis (OA) patients at the age of 65 years and above. Endothelin-1 (ET-1), known as a potent vasoconstrictor, has been implicated in pathogenesis of essential hypertension and diabetic vascular complications. High level of ET-1 was observed in osteoarthritic cartilage. The unanswered question was whether the sustained high level of ET-1 would induce development of OA. This study aimed to investigate the phenotypes of articular cartilage and subchondral bone in transgenic mice with endothelial cellspecific overexpression of ET-1 (TET-1 mice). Materials and Methods: Male heterozygous TET-1 mice were generated by microinjection of the ET-1 construct driven by Tie-1 promoter. These TET-1 mice developed systemic hypertension with altered vascular reactivity since 8 weeks after birth. Tibiae of male, heterozygous TET-1 mice (n = 4) and their littermates (n = 4) of 35-week-old were obtained. Microcomputed tomographic (Micro-CT) scan on tibiae were performed before tissue processed to wax blocks. Tibiae in wax blocks were sectioned for histology. Results: The Micro-CT data showed a decrease of mean (± standard deviation) trabecular bone density (10.9 ± 0.4%) in primary spongiosa of TET-1 mice compared with the littermates (12.8 ± 0.5%; p < 0.05). Histologically, articular chondrocytes underwent hypertrophic changes together with thickening of calcified cartilage in TET-1 mice when compared with their littermates. Discussion and Conclusion: Endothelial-specific overexpression of ET-1 induced OA-like changes, which might be a therapeutic target.