Chondrocytes, synoviocytes and dermal fibroblasts all express PH-20, a hyaluronidase active at neutral pH

Hyaluronan (HA), a linear, megadalton glycosaminoglycan, has important biological and structural functions [1]. First, by interacting with transmembrane proteins, such as CD44 and other members of the heterogeneous group of proteins termed hyaladherins, HA initiates signaling pathways and contributes to the formation of the pericellular matrix that prevents direct contact between cells and protects them against attack from viruses, bacteria, and immune cells. Second, in the extracellular matrix further removed from the cell and in the basement membrane, the hydrophilic HA network not only gives turgor pressure and resilience, but also functions as a scaffold about which other macromolecules associate and orient themselves [2-4]. Within the abundant extracellular matrix of articular cartilage, the long, filamentous HA molecules form the backbone upon which the viscoelastic aggrecan molecules align to form aggregates, a supramolecular organization that immobilizes aggrecans at very high concentrations within the collagen network, thereby providing remarkable biomechanical properties to the articular tissue [5]. Third, in its unaggregated form, HA is the major macromolecular species in synovial fluid, being thereby responsible for the viscoelastic properties of what is otherwise a simple plasma diffusate [6].On the other hand, because HA degradation products may interact with various cells and initiate a program of gene expression leading to cell proliferation, migration, or activation [3,4,7], these products exhibit biological functions that are quite distinct from those of the native, high-molecular-weight polymer. Thus, by stimulating the proliferation and migration of vascular endothelial cells via multiple signaling pathways, HA fragments induce angiogenesis, whereas high-molecular-weight HA inhibits angiogenesis [8,9]. Studies in vitro have also indicated that HA fragments similar in size to that of fragmented HA molecules found in vivo in inflammatory sites indu