Chain Gangs: New Aspects of Hyaluronan Metabolism

Abstract

Hyaluronan is a matrix polymer prominent in tissues undergoing rapid growth, development, and repair, in embryology and during malignant progression. It reaches 107 Daltons in size but also exists in fragmented forms with size-specific actions. It has intracellular forms whose functions are less well known. Hyaluronan occurs in all vertebrate tissues with 50% present in skin. Hyaluronan provides a scaffold on which sulfated proteoglycans and matrix proteins are organized. These supramolecular structures are able to entrap water and ions to provide tissues with hydration and turgor. Hyaluronan is recognized by membrane receptors that trigger intracellular signaling pathways regulating proliferation, migration, and differentiation. Cell responses are often dependent on polymer size. Catabolic turnover occurs by hyaluronidases and by free radicals, though proportions between these have not been determined. New aspects of hyaluronan biology have recently become realized: involvement in autophagy, in the pathology of diabetes., the ability to modulate immune responses through effects on T regulatory cells and, in its fragmented forms, by being able to engage several toll-like receptors. It is also apparent that hyaluronan synthases and hyaluronidases are regulated at many more levels than previously realized, and that the several hyaluronidases have functions in addition to their enzymatic activities.

Effect of radiotherapy on expression of hyaluronan and EGFR and presence of mast cells in squamous cell carcinoma of the head and neck

“…Earlier studies have shown that staining intensity correlates with the expression of HA (19). Our results confirm the earlier findings of cytoplasmic HA and EGFR, although their role in the cytoplasm is still unclear (20). Membranous staining of EGFR has been shown in clinical studies to correlate with cervical lymph node metastases and survival (21,22).…”

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…Hyaluronan occurs as a high molecular weight (HMW) 2 polymer, reaching Ͼ10 6 -10 7 Da, but it also exists in much smaller forms (2). Under physiological conditions, stable levels of HA are regulated locally by the opposing activities of HA synthases and hyaluronidases, whereas its systemic metabolism is controlled by liver and kidneys (2).…”

“…Hyaluronan occurs as a high molecular weight (HMW) 2 polymer, reaching Ͼ10 6 -10 7 Da, but it also exists in much smaller forms (2). Under physiological conditions, stable levels of HA are regulated locally by the opposing activities of HA synthases and hyaluronidases, whereas its systemic metabolism is controlled by liver and kidneys (2). During acute and chronic inflammation or tissue injury, reactive oxygen species (3) and matrix metalloproteinases (4) can significantly alter the HA turnover, generating local (5,6) and systemic (7,8) accumulation of low molecular weight HA (LMW HA) fragments.…”

Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells

“…Three main isoforms of HA synthases (HAS), namely HAS1, HAS2 and HAS3, are responsible for the synthesis of different-sized HA on cell membranes in mammalian tissues and these isoforms have 55%-71% of amino acid sequences in common in their structures (Weigel and DeAngelis 2007;Itano 2008;Erickson and Stern 2012;Bernert 2013). Large-sized HA (>2 × 106 Da) is synthesised by HAS2, whereas smaller-sized HA (between 2 × 105 and 2 × 106 Da) are synthesised by HAS1 and HAS3 (Itano and Kimata 2002).…”