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Regulation of hyaluronan secretion into rabbit synovial joints in vivo by protein kinase C

C. L. Anggiansah, D. Scott, A. Poli, P. J. Coleman, E. Badrick, R. M. Mason* and J. R. Levick

Hyaluronan (HA) is important for joint cavitation, lubrication, volume regulation and synovial fluid drainage but little is known about the regulation of joint HA synthesis/secretion in vivo. We investigated whether HA secretion into joints in vivo can be regulated by protein kinase C (PKC). Secretion into the knee joint cavity of anaesthetised rabbits was measured over 6 h by washout and chromatography. Joints received intra-articular injections of Ringer vehicle (control) or an activator of classical PKC isoforms, phorbol-12-myristate-13-acetate (PMA), at 20-2000 ng ml^-1. The effects of PKC inhibition by bisindolylmaleimide (BIM) and protein synthesis inhibition by cycloheximide (CX) on basal and stimulated HA secretion were also studied. The endogenous HA mass, 181 ± 8 µg (n = 26, mean ± S.E.M.), and basal secretion rate, 4.4 ± 0.4 µg h^-1, indicated a turnover time of 41 h. Secretion rate showed a dose-dependent response to PMA (n = 30), rising 5-fold to 21.7 ± 5.0 µg h^-1 (n = 5) at 2000 ng ml^-1 PMA (P < 0.0001, one-way ANOVA). PMA-induced stimulation was partially suppressed by CX (HA secretion: 5.8 ± 1.7 µg h^-1, n = 8, P < 0.01) and totally blocked by BIM (HA secretion: 3.2 ± 0.6 µg h^-1, n = 9, P < 0.001). Basal HA secretion was unaffected by CX over 6 h (4.2 ± 0.7 µg h^-1, n = 8) but was reduced by 29 % by BIM (3.1 ± 0.6 µg h^-1, n = 10, P = 0.03). It is concluded that: (1) PKC can stimulate HA secretion into joints in vivo through mechanisms involving protein synthesis de novo as well as phosphorylation; (2) basal HA secretion is only partially PKC dependent; and (3) hyaluronan synthase turnover time is > 6 h in vivo, which is slower than in vitro (< 2-3 h).

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