Glycosaminoglycans

Glycosaminoglycans are complex linear polysaccharides that are covalently attached to core proteins, except for hyaluronan, to form proteoglycans. ^[1] They are long linear and complex polysaccharides that are fundamental components of the mammalian extracellular matrix. ^[2] Hyaluronan is a non-sulfated, naturally occurring non-protein glycosaminoglycan with distinct physico-chemical properties, produced by synoviocytes, fibroblasts, and chondrocytes. ^[3]

Glycosaminoglycans organize the extracellular matrix, contribute to cell-matrix interactions, and regulate cell signaling. ^[4] 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. ^[5] Metabolic pathways for biosynthesis and degradation tightly control the turnover rate, concentration, and molecular size of hyaluronan in tissues, and its wide range of molecular weights mediate diverse functions that depend on molecular size and tissue concentration. ^[5] Proteoglycans are classified by cellular and subcellular location into four major families with distinct forms and functions: the intracellular, cell-surface, pericellular, and extracellular proteoglycans. ^[6]

Hyaluronic acid is an important component of the extracellular matrix, with loss starting at 25 years old, and exposome factors affect its synthesis and degradation in skin aging. ^[7] The concentration of hyaluronic acid and its molecular weight decline as osteoarthritis progresses with aging. ^[3] In the intervertebral disc, increasing age is accompanied by loss of water from the matrix and a change and diminution in proteoglycan content, so that the disc becomes less gelatinous and more fibrous. ^[8] Naked mole rats, renowned for their exceptional longevity and maintenance of health, accumulate very high molecular weight hyaluronan in their tissues, which is attributed to higher processing and production by some hyaluronan synthases along with lower degradation by certain hyaluronidases and indirectly confers resistance to conditions such as cancer. ^[9]

Hyaluronic acid has been used for more than four decades in the treatment of osteoarthritis in dogs, horses, and humans, producing anti-arthritic effects via multiple mechanisms involving receptors, enzymes, and other metabolic pathways. ^[3] Analysis of glycosaminoglycan interaction networks gives insight into the molecular and cellular mechanisms underlying their functions, and these interactomes can be used to design inhibitors targeting specific GAG interactions for therapeutic purpose. ^[4] Clinical studies indicate that topical hyaluronic acid is both well tolerated and effective for improving skin hydration and rejuvenation and as an adjuvant to post-surgical and facial rejuvenation procedures. ^[7]