MINIREVIEW SERIES Regulatory roles of hyaluronan in health and disease Vincent Hascall 1 and Nikos Karamanos 2,3 1 Cleveland Clinic Lerner College of Medicine, Biomedical Engineering ND-20, Cleveland, OH, USA 2 Department of Chemistry, Laboratory of Biochemistry, University of Patras, Greece 3 Foundation of Research and Technology (FORTH ⁄ ICE-HT), Greece The glycosaminoglycan hyaluronan (HA) is a major com- ponent of extracellular matrices with many diverse func- tions that depend on its chain size and its interactions with various effective proteins and cell receptors. Such interactions trigger several intracellular signaling path- ways that regulate growth, differentiation and migration. HA is implicated in physiological and pathological pro- cesses, including embryogenesis, morphogenesis, wound healing, tissue repair, inflammation and the progression of several diseases, among them cancer and diabetes. Recent data suggest a regulatory role of HA in cancer cell migration, invasion and metastasis, and implicate its interaction with variants of the cell surface HA receptor CD44 in the molecular targeting of solid tumors. HA research areas are expanding so rapidly that it is not pos- sible to cover all HA functions. The three thematic mini- reviews, however, provide the reader with focused assessments of the current HA research areas. The first minireview by Wang et al. focuses on the dis- covery of monocyte-adhesive HA matrices and how they have morphed into various pathologies, including inflam- matory bowel disease, wound healing, asthma and diabe- tes. Notably, the unique mechanism by which HA is normally synthesized, namely the utilization of cytosolic substrates with extrusion of the growing HA polymer into the extracellular matrix, has a major role in its large vari- ety of normal and pathological functions. This is an emerging area of research that will impact on most, if not all, inflammatory processes. The second minireview by Tammi et al. focuses on the novel regulatory points in HA synthesis that have recently been discovered. Furthermore, it highlights the role of several factors influencing the expression of the HA syn- thases (HASs), as well as the transcriptional events in the HAS gene promoter, traffic of HAS from the Golgi appa- ratus to the plasma membrane, post-translational modifi- cations of the HAS protein and the pivotal role of the UDP-sugars as HAS substrates and feedback controllers of HAS expression. As the accumulation of HA in malig- nant tumors promotes their growth and spread, the iden- tification of control points of HA synthesis may offer opportunities for drug development. The third minireview by Misra et al. focuses on new aspects concerning the interaction of HA with CD44 vari- ants (CD44v) and how this interaction triggers several intra- cellular signaling pathways regulating proliferation, migration and differentiation. Reactive stroma in cancer is often characterized by an increase in cancer-associated fibroblasts ⁄ myofibroblasts, which produce an array of growth factors and chemokines that amplify the synthesis of HA. The interaction of HA with CD44v facilitates cancer progression and invasion ⁄ metastasis with respect to stromal HA crosstalk with epithelium CD44v. This minireview high- lights recent findings in tumor–stromal interactions and their possible roles in HA–CD44v-induced tumor growth and invasion, together with fresh insights into the enigmatic nature of CD44 splice variants, and how the suppression of HA–CD44v interaction may be a novel therapeutic target. We hope that this thematic minireview series will bring these emerging concepts to the readers, will highlight the importance of HA in the signaling and regulation of cellu- lar events, and will stimulate new studies in this very interesting research area that will provide a deeper under- standing of disease progression and treatment. Dr Hascall is a staff member of the Department of Biomedical Engineering and Orthopedic Surgery at the Cleveland Clinic, Cleveland, Ohio, and a Professor of Biological Chemistry at Case Western Reserve University. He is currently an Associate Editor for the Journal of Biological Chemistry. His current research interests include connective tissue biology and the role of HA matrices in inflammations. Dr Hascall is a co-founder of the International Society for Hyaluronan Sciences (ISHAS) and has authored over 250 papers and book chapters on the structure and function of proteoglycans and HA, and their involvement in tissue organization and function. He has received honorary degrees at the University of Lund, Sweden, and the University of Kuopio, Finland, and was honored by the University of Patras, Greece, in 2009. Dr Karamanos is a Professor of Biochemistry at the University of Patras, Greece. He has been the driving force in coordi- nating the Meetings of Matrix Biology, the FEBS Advanced Lecture Courses on Matrix Pathobiology, Signaling and Molecular Targets in Greece. His current research interests include the importance of proteoglycans, glycosaminoglycans and metalloproteinases in cell signaling and in the molecular targeting of cancer. Dr Karamanos has published more than 200 papers and book chapters and is the Vice-President of the Hellenic Society of Biochemistry and Molecular Biology, the contact person for the Federation of Connective Tissue Societies, and the current Head of the Department of Chem- istry, University of Patras. doi: 10.1111/j.1742-4658.2011.08068.x FEBS Journal 278 (2011) 1411 ª 2011 The Authors Journal compilation ª 2011 FEBS 1411 . MINIREVIEW SERIES Regulatory roles of hyaluronan in health and disease Vincent Hascall 1 and Nikos Karamanos 2,3 1 Cleveland Clinic Lerner College of. research interests include the importance of proteoglycans, glycosaminoglycans and metalloproteinases in cell signaling and in the molecular targeting of cancer.