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Multiple aggrecan molecules are organized in the extracellular matrix via a domain-specific molecular interaction with hyaluronan and a link protein, and these high molecular weight aggregates are immobilized within the collagen and glycoproteinnetwork. The high negative charge density of glycosaminoglycans provides hydrophilicity, high osmotic swelling pressure and conformational flexibility, which together function to absorb fluctuations in biomechanical stresses on cartilage\u00a0during movement of an articular joint. We have summarized information on the history and current knowledge obtained by biochemical and genetic approaches, on cell-mediated regulation of aggrecan metabolism and its role in skeletal development, growth as well as during\u00a0the development of joint disease. In addition, we describe the pathways for hyaluronan metabolism, with particular focus on the role as a \u201cmetabolicrheostat\u201d during chondrocyte responses in cartilage remodeling in growth and disease.<\/jats:p><jats:p>Future advances in effective therapeutic targeting of cartilage loss during osteoarthritic\u00a0diseases of the joint as an organ as well as in cartilage tissue engineering would benefit from \u2018big data\u2019 approaches and bioinformatics, to uncover novel feed-forward and feed-back mechanisms for regulating transcription and translation of genes and their integration into cell-specific pathways.<\/jats:p>","DOI":"10.1007\/978-3-031-25588-5_1","type":"book-chapter","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T08:02:51Z","timestamp":1681372971000},"page":"3-29","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Aggrecan and Hyaluronan: The Infamous Cartilage Polyelectrolytes \u2013 Then and Now"],"prefix":"10.1007","author":[{"given":"Anna H. 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