Abstracts Category : Other

Role of endothelin-1 in chondrocyte differentiation andcartilage homeostasis

by Weiwei Zhao

Currently, osteoarthritis (OA) is recognized as aheterogeneous disease with a variety of causes. The initiation andprogression of OA cannot be accounted for by mechanical stressalone. There is an increasing body of evidence showing thatsystemic conditions, such as chronic inflammation and metabolicdisorders, contribute to the development of OA. Given the highfrequency of OAs co-occurrence with cardiovascular diseases (CVDs)and metabolic syndrome (MetS), special attention has been paid tostudying the common mechanisms underlying those systemic diseases.Unraveling the common biological pathways would benefit ourunderstanding of the pathogenesis of metabolic OA as well as thedevelopment of novel drugs for OA treatment. The view thatendothelin-1 (ET-1) plays a critical role in the cardiovascularsystem arose from a number of observations that levels of plasmaET-1 were found to be significantly upregulated in patients withCVDs and MetS. More recently, it was suggested that ET-1 promotedcartilage degradation via collagenase upregulation. Thereby, wehypothesized that the alteration of systemic ET-1 would affect thevascular functions as well as the cartilage homeostasis. In thisstudy, we aimed to investigate the role of ET-1 in chondrocytedifferentiation and cartilage homeostasis. The predominantexpression of ET-1 in hypertrophic chondrocytes was detected,suggesting the association of ET-1 signaling with chondrocytehypertrophy. The overexpression of endothelial ET-1 resulted inslight dwarfism in neonatal mice, which was attributed to theactivity of ET-1 in endochondral ossification initiated by thehypertrophic differentiation of chondrocytes. Age-relatedspontaneous cartilage degeneration was found in transgenic miceoverexpressing endothelial ET-1 (TET-1 mice), suggesting that theelevation of systemic ET-1 affected the homeostasis of articularcartilage. An increased number of type collagen positivechondrocytes in un-calcified cartilage was identified. Furthermore,accelerated progression of traumatic OA was observed in TET-1 mice.In vitro study showed that ET-1 facilitated chondrocyte hypertrophyby increasing the expression of hypertrophic markers. These resultssuggested increased ET-1 promoted cartilage degeneration probablyvia the regulation of chondrocyte hypertrophy. Taken together, wehave demonstrated the role of systemic ET-1 in chondrocytehypertrophy, endochondral ossification, cartilage maintenance, andOA. This is the first in vivo study to investigate the effect ofelevated systemic ET-1 on chondrocytes and cartilage, contributingto the knowledge about ET-1s role in the skeletalsystem. published_or_final_version Orthopaedics and Traumatology Doctoral Doctor of Philosophy