New molecules indispensable for hyaluronan degradation, HYBID (CEMIP/KIAA1199) and TMEM2 (CEMIP2): Differential roles in physiological and pathological non-neoplastic conditions.

The biological activity of hyaluronan (HA), a major component of the extracellular matrix in vertebrate tissues, depends on its molecular weight, and thus its degradation is a critical process for HA biological functions. Here, we review the characteristics of newly discovered proteins essential for HA degradation, hyaluronan-binding protein involved in hyaluronan depolymerization (HYBID), also known as cell migration inducing hyaluronidase 1 (CEMIP) and KIAA1199, and transmembrane protein-2 (TMEM2; alias CEMIP2). Human and mouse forms of HYBID exert their HA-degrading activity in special microenvironments including recycling endosomes. Mouse TMEM2 functions as a cell-surface hyaluronidase for HA turnover in local tissues, lymph nodes, and the liver. In contrast, the role of human TMEM2 in HA degradation is the subject of much debate. HYBID expression is upregulated by proinflammatory factors such as histamine and interleukin-6 and downregulated by transforming growth factor-β. HYBID is involved in physiological HA turnover in human skin and joint tissues and plays an important role in their pathological destruction by accelerating HA degradation.