67. Combined beta-adrenergic-receptor (AR) agonist and alpha-AR antagonist treatment reduced joint damage in adjuvant-induced arthritis without affecting disease-induced sympathetic denervation of the ankle

Abstract

Combined treatment with terbutaline, a beta-AR agonist, and phentolamine, a alpha-AR antagonist, (SH1293) after disease onset reduced disease severity in rats with adjuvant-induced arthritis (AA) (Lubahn et al., 2004). Here, we investigated the effects of SH1293 on sympathetic innervation and bone integrity in the ankle joint. On day (D) 0, male Lewis rats were immunized with complete Freund’s adjuvant to induce AA. From D12 (disease onset) through D21 or D28, rats were intraperitoneally treated twice-daily with vehicle or SH1293 (1200 mg terbutaline and 125 mg phentolamine/day in 250 ml). Ankle joints were evaluated for lymphocyte infiltration, bone area and volume, osteoclast number, cartilage and pannus area using routine histology, and sympathetic innervation using immunohistochemistry for tyrosine hydroxylase. SH1293 preserved cartilage area, and bone volume (D21 and D28) and reduced pannus formation and synovial lymphocyte infiltration compared with controls. Bone area and osteoclast counts revealed high and low responders to SH1293. High-responders had increased bone area and lower osteoclast numbers. AA reduced sympathetic nerve density, an effect transiently attenuated by SH1293. No significant correlations were observed between variables for joint destruction and between nerve density and these variables with SH1293 treatment. Collectively, these findings are consistent with reports in RA patients, and support sympathetic regulation in disease-mediated joint destruction that can be targeted with adrenergic receptor drugs for therapeutic benefits in autoimmune arthritis.