| Abstract | We have previously shown that endogenous Urocortin (Ucn) is an essential chondrocyte survival signal as depletion with a Ucn specific antibody or receptor blockade with a pan CRF receptor antagonist (alpha-helical CRH) results in significant chondrocyte apoptosis. RT-PCR and western blot analysis have shown expression of Ucn system ligands and receptors in both a human chondrocyte cell line and primary human chondrocytes, including the expression of both CRFR1 and CRFR2 receptor subtypes. Unlike other members of the Ucn family (Ucn II and Ucn III) which are specific CRFR2 agonists, Ucn has been shown to bind to both CRFR1 and CRFR2 so we therefore sought to determine the relative importance of Ucn agonism at each receptor subtype. To this end, apoptosis induction by alpha-helical CRH was compared to the effects of the selective antagonists CP154526 (CRFR1) and Astressin2B (CRFR2). Concomitant treatment with both antagonists resulted in a dose dependent increase in chondrocyte apoptosis, similar to that seen with alpha helical CRH as dis treatment with CP154526 alone whereas treatment with Astressin 2B showed no significant increase in apoptosis as compared to the control. Taken together, these data suggest that Ucn mediated chondroprotection is therefore primarily a property of CRFR1 mediated events. |
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