Hyaluronan‐binding proteins in development, tissue homeostasis, and disease

The high molecular weight glycosaminoglycan hyaluronan plays an important role in tissue remodeling during development, normal tissue homeostasis, and disease. The interaction of hyaluronan with matrix hyaluronan-binding proteins and cell-surface hyaluronan receptors regulates many aspects of cell behavior such as cell migration, cell-cell adhesion, and cell differentiation. Hyaluronan-binding proteins have been grouped together as a family termed hyaladherins--further subdivided in matrix and cell-surface hyaladherins (receptors). Specific hyaluronan-hyaladherin interactions that affect cell behavior are the focus of this review. Both clearance and turnover of hyaluronan involve hyaluronan receptor-mediated endocytosis. Pericellular matrix assembly and retention on many cells, especially chondrocytes, are mediated by hyaluronan receptors, in coordination with other matrix hyaladherins. Hyaluronan can also have an independent, direct effect on cell-to-cell adhesion as well as migration, again mediated by specific cell-surface hyaluronan receptors. This is especially apparent in tumor cells, where metastatic potential is correlated with hyaluronan receptor expression. As migrating cells encounter new environments enriched in matrix hyaladherins, the capacity for matrix assembly may terminate cell migration. Thus, the temporal/spatial deposition of particular matrix hyaladherins also serves as signals or matrix cues to alter cell behavior.