SECRETORY REGULATION IN VIVO, MOLECULAR REFLECTION & HYDRAULIC ROLES OF SYNOVIAL HYALURONAN

ABSTRACT Hyaluronan occurs both in the synovial lining as a component of the interstitial matrix and in synovial fluid as a mobile solute. In both sites hyaluronan has a key role in the regulation of joint fluid balance, but by different mechanisms, as follows. 1] Hyaluronan in joint lining matrix confers a high hydraulic resistance on synovium, which is crucial to its synovial fluid-encapsulating function. Hyaluronan's contribution grossly exceeds its hydraulic drag, perhaps due to an organisational role in the matrix. 2] Hyaluronan secretion in vivo is stimulated by joint distension and by protein kinase C (PKC) activation. The latter is only partially inhibited by cycloheximide. A mechanosensitive regulatory pathway is inferred. 3] The high concentration of hyaluronan in synovial fluid is generated not by a high secretion rate but by the partial reflection of hyaluronan by synovium as fluid drains out of the cavity. This increases the working lifetime of hyaluronan in joint fluid up to 20times. 4] The reflection of hyaluronan by synovium during fluid drainage creates a dynamic concentration-polarisation layer, the osmotic pressure of which opposes joint fluid pressure. As a result, the rate of synovial fluid loss scarcely increases with pressure over a wide range, protecting joints from squeezing themselves dry during sustained flexion.