BBB seminar: J. Rodney Levick

J. Rodney Levick
Professor, Department of Physiology, St. George's Hospital Medical School, London, UK

Synovial fluid, the vital nutritive and lubricating liquid inside a joint, turns over in a few hours. Synovial fluid hyaluronan (HA), which is secreted by synoviocytes, has a key role in joint fluid balance, as well as lubrication. Fluid drains out of the joint cavity when pressure is raised, e.g. on flexion, so a mechanism is needed to prevent the joint from drying out. HA does this by rendering the drainage rate astonishingly insensitive to pressure. The graded, dynamic opposition to outflow ('buffering') is attributed to the molecular sieving of HA by synovial interstitium. This creates a high surface HA concentration and osmotic pressure (concentration polarisation theory), boosting local mechanoprotection. The lecture reviews recent evidence for the concentration polarisation theory and new findings on the mechanosensitive regulation of HA secretion into joints.The key assumption that HA is partly reflected by synovium was tested in vivo by analysing intra-articular fluid, subsynovial fluid and lymph during pressure-driven filtration of HA across rabbit knee synovium. Downstream dilution and upstream accumulation proved that synovium does indeed partially reflect and sieve out HA molecules. If concentration polarisation exists, the downstream [HA] should rise when filtration rate is increased (cf. plateau if no concentration polarisation). This proved to be the case, and indicated a high reflection coefficient, ~ 0.9. Reduction of HA concentration and chainlength, which occur in arthritis, attenuate reflection and outflow buffering.Since a small amount of HA escapes into lymph, the joint has to secrete HA continuously to replace the loss. The secretion rate is linked to joint use, being increased by cyclic movement. Stretch-stimulated HA secretion is also seen in primary cultured rabbit synoviocytes, though hyaluronan synthase 2 expression (main isoform) is not detectably increased. A series of studies showed that the stretch-stimulated HA secretion depends on extracellular Ca2+ influx, which triggers the membrane translocation of Ca2+-dependent protein kinase Ca, leading to ERK1/2 phosphorylation. Current work is thus revealing a regulatory pathway that links HA secretion to joint use, raising future possibilities for therapeutic intervention into HA secretion.