title: Transforming growth factor-alpha induces endothelin receptor A expression in osteoarthritis.
abstract: Previously, our lab identified transforming growth factor-alpha (TGFα) as a novel factor involved in osteoarthritis (OA) in a surgical model of the disease. In the same study, we also observed increased transcript levels for endothelin receptor A (ET(A)R), a known contributor to cartilage pathology. To investigate the connection between TGFα and endothelin signaling in OA, primary articular chondrocytes and osteochondral explants were isolated from Sprague-Dawley rats and treated with vehicle or TGFα. Expression of ET(A)R protein and its encoding gene Ednra was assessed. Chondrocytes and cartilage explants were also treated with the endothelin receptor A/B antagonist Bosentan, in order to determine whether TGFα effects could be blocked. TGFα induced expression of ET(A)R protein and its encoding gene Ednra. In primary chondrocyte cultures, Bosentan did not block TGFα responses of the anabolic genes Sox9, Agc1, and Col2a1, but reduced the induction of Mmp13 and Ednra transcripts by TGFα. In osteochondral explants, the inhibitor partially blocked TGFα reduction of type II collagen, as well as induction of MMP-13 and type II collagen neoepitopes. TGFα induces ET(A)R expression in articular chondrocytes and receptor antagonism appears to block some TGFα-induced catabolic effects in a three-dimensional organ culture system. Thus, TGFα may be a therapeutic target upstream of ET(A)R in OA.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada, N6A 5C1.
authors.forename: Shirine E
authors.initials: SE
authors.lastname: Usmani
authors.forename: C Thomas G
authors.initials: CT
authors.lastname: Appleton
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents; D000077300:Bosentan; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009924:Organ Culture Techniques; D010003:Osteoarthritis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D013449:Sulfonamides; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D016328:NF-kappa B; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D016211:Transforming Growth Factor alpha; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000077300:Bosentan