title: Signal pathways regulating hyaluronan secretion into static and cycled synovial joints of rabbits.
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 ( ) 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 . Similar or larger increases were elicited in static joints by the intra-articular Ca(2+) ionophore ionomycin, prostaglandin E(2), 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 . The ENaC channel blocker amiloride inhibited MSHA, whereas other inhibitors of stretch-activated channels (Gd(3+), 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.
authors.affiliation: Physiology, Basic Medical Sciences, St George's Hospital Medical School, University of London, London SW17 0RE, UK.
authors.forename: K R
authors.initials: KR
authors.lastname: Ingram
authors.forename: A K T
authors.initials: AK
authors.lastname: Wann
authors.forename: R M
authors.initials: RM
authors.lastname: Wingate
authors.forename: P J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: N
authors.initials: N
authors.lastname: McHale
authors.forename: J R
authors.initials: JR
authors.lastname: Levick
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D007596:Joints / Q000378:metabolism*; D009068:Movement / Q000502:physiology*; D010740:Phospholipases / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism*
chemical_list: D006820:Hyaluronic Acid; D010740:Phospholipases; D002118:Calcium