This review summarizes the genetic alterations and knockdown approaches published in the literature to assess the role of key proteoglycans and glycoproteins in the structural development, function, and repair of tendon, ligament, and enthesis. The information was collected from (i) genetically altered mice, (ii) in vitro knockdown studies, (iii) genetic variants predisposition to injury, and (iv) human genetic diseases. The genes reviewed are for small leucine-rich proteoglycans (lumican, fibromodulin, biglycan, decorin, and asporin); dermatan sulfate epimerase (Dse) that alters structure of glycosaminoglycan and hence the function of small leucine-rich proteoglycans by converting glucuronic to iduronic acid; matricellular proteins (thrombospondin 2, secreted phosphoprotein 1 (Spp1), secreted protein acidic and rich in cysteine (Sparc), periostin, and tenascin X) including human tenascin C variants; and others, such as tenomodulin, leukocyte cell derived chemotaxin 1 (chondromodulin-I, ChM-I), CD44 antigen (Cd44), lubricin (Prg4), and aggrecan degrading gene, a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5 (Adamts5). Understanding these genes represents drug targets for disrupting pathological mechanisms that lead to tendinopathy, ligamentopathy, enthesopathy, enthesitis and tendon/ligament injury, that is, osteoarthritis and ankylosing spondylitis. 1. Introduction 1.1. Proteoglycans and Glycoproteins Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a core protein with one or more covalently attached GAG chain(s) at specific site(s) [1]. The GAG chains comprise disaccharide units composed of aminoglycan and uronic acid (glucuronic and or iduronic acid) [2]. The chains are long, linear carbohydrate polymers that are negatively charged under physiological conditions, due to the occurrence of sulfate and uronic acid groups. Proteoglycans occur in the connective tissue. Glycoproteins, on the other hand, are proteins that contain oligosaccharide glycans attached to polypeptide side chains covalently. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification via glycosylation. Secreted extracellular proteins are often glycosylated [3]. In the proteins that have extracellular segments, those segments are also glycosylated. Glycoproteins are often important integral membrane proteins, where they play a role in cell-cell interactions. 1.2. Tendon, Ligament, and Enthesis A tendon is a compositionally complex tissue with a
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