EXTL2, one of the three EXT-like genes in the human genome homologous to EXT1 and EXT2, encodes an N-acetylhexosaminyltransferase. It is involved in glycosaminoglycan (GAG) biosynthesis, a process crucial for various biological functions such as cell-extracellular matrix crosstalk and cell signaling regulation [1,4,5]. Genetic models, like knockout mice, have been valuable in studying its function.

In EXTL2-knockout mice, GAG production was significantly higher than in wild-type mice [1,4,5]. Under CCl4-induced liver failure, hepatocyte proliferation was lower in EXTL2-knockout mice, impairing liver regeneration. This was due in part to reduced hepatocyte-growth-factor-mediated signaling [1,5]. In an induced chronic kidney disease model, matrix mineralization in vascular smooth muscle cells of EXTL2-knockout mice was enhanced, as altered GAG biosynthesis affected bone-morphogenetic-protein signaling and increased the differentiation of VSMCs into osteoblasts [1]. In gastric cancer cell models, KO of EXTL2 enhanced HS levels, promoted a more aggressive phenotype with higher motility and invasion, and impaired Ephrin type-A 4 receptor activation [2]. In a spinal cord demyelinating injury model, EXTL2 -/- mice had excessive CSPG deposition, exacerbated axonal damage, myelin disruption, and increased microglia/macrophages within lesions [3].

In conclusion, EXTL2 plays a key role in regulating GAG biosynthesis. The use of EXTL2 knockout mouse models has revealed its significance in processes related to liver regeneration, aortic calcification, cancer cell behavior, and neuroinflammation following demyelination. These findings contribute to understanding the underlying mechanisms of related diseases and may offer potential therapeutic targets.