Abstract
As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis and degradation tightly control the turnover rate, concentration, and molecular size of hyaluronan in tissues. Despite the relatively simple chemical composition of this polysaccharide, its wide range of molecular weights mediate diverse functions that depend on molecular size and tissue concentration. Genetic engineering and pharmacological approaches have demonstrated close associations between hyaluronan metabolism and functions in many physiological and pathological events, including morphogenesis, wound healing, and inflammation. Moreover, emerging evidence has suggested that the accumulation of hyaluronan extracellular matrix and fragments due to the altered expression of hyaluronan synthases and hyaluronidases potentiates cancer development and progression by remodeling the tumor microenvironment. In addition to the well-known functions exerted by extracellular hyaluronan, recent metabolomic approaches have also revealed that its synthesis can regulate cellular functions via the reprogramming of cellular metabolism. This review highlights the current advances in knowledge on the biosynthesis and catabolism of hyaluronan and describes the diverse functions associated with hyaluronan metabolism.
Highlights
Hyaluronan (HA) comprises a major component of the extracellular matrix (ECM) in vertebrate connective tissues and is abundant in the cartilage, skin, brain, vitreous body, umbilical cord, and synovial fluid
With a broad molecular weight range, HA has multiple physical and physiological properties that depend on its molecular weight and concentration, both of which are regulated by the balance between HA biosynthesis and degradation [5]
Sivakumar et al demonstrated that covalent binding of HA and inter-α-trypsin inhibitor (IαI) mediated by tumor necrosis factor-stimulated gene-6 (TSG-6) promoted the accumulation of HA ECM on the right side of the dorsal mesentery (DM) [65]
Summary
Hyaluronan (HA) comprises a major component of the extracellular matrix (ECM) in vertebrate connective tissues and is abundant in the cartilage, skin, brain, vitreous body, umbilical cord, and synovial fluid. Since HA was first discovered in bovine vitreous as a novel glycosaminoglycan [1], its structure, physical properties, physiological activity, and metabolism have been studied for almost a century. The concentration and size distribution of HA vary with tissue type, age, and disease severity [3,4]. With a broad molecular weight range, HA has multiple physical and physiological properties that depend on its molecular weight and concentration, both of which are regulated by the balance between HA biosynthesis and degradation [5]. The dynamic metabolism of HA is tightly controlled by three synthases and several hyaluronidases [5]. The HA receptor CD44 participates in many physiological and pathological processes by interacting with HA and activating key signaling cascades [15] (Figure 2). Biomolecules 2020, 10, 1525 associations between HA metabolism and functions, referring to recent discoveries in metabolic reprogramming coupled with HA production
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