Signal pathways regulating hyaluronan secretion into static and cycled synovial joints of rabbits

Ingram, K.R., Wann, A.K.T., Wingate, R.M., Coleman, P.J., McHale, N. and Levick, J.R. (2009) Signal pathways regulating hyaluronan secretion into static and cycled synovial joints of rabbits. The Journal of Physiology, 587 (17), 4361-4376. (doi:10.1113/JPHYSIOL.2009.175620).

Abstract

Joint lubrication, synovial fluid conservation and many pathophysiological processes depend on hyaluronan (HA). Intra-articular HA injection and exercise, which stimulates articular HA production, ameliorate osteoarthritis. We therefore investigated the pathways regulating movement-stimulated articular HA secretion rate (inline image) in vivo. Endogenous HA was removed from the knee joint cavity of anaesthetised rabbits by washout. Joints were then cycled passively or remained static for 5 h, with/without intra-articular agonist/inhibitor, after which newly secreted HA was harvested for analysis. Movement almost doubled inline image. Similar or larger increases were elicited in static joints by the intra-articular Ca2+ ionophore ionomycin, prostaglandin E2, cAMP-raising agents, serine/threonine phosphatase inhibitor and activation of protein kinase C (PKC). PKC-stimulated secretion was inhibited by the PKC inhibitor bisindolylmaleimide I and inhibitors of the downstream kinases MEK-ERK (U0126, PD98059). These agents inhibited movement-stimulated secretion of HA (MSHA) only when the parallel p38 kinase path was simultaneously inhibited by SB203580 (ineffective alone). The phospholipase C inhibitor U73122 almost fully blocked MSHA (P= 0.001, n= 10), without affecting static inline image. The ENaC channel blocker amiloride inhibited MSHA, whereas other inhibitors of stretch-activated channels (Gd3+, ruthenium red, SKF96365) did not. It is proposed that MSHA may be mediated by PLC activation, leading to activation of parallel PKC–MEK–ERK and p38 kinase pathways.

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Contributors

Author: A.K.T. Wann

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