Abstract
Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.
Highlights
Sulfated compounds include a wide array of substances, ranging in molecular weight from less than 103 Da to greater than 106 Da, that undergo striking changes in their physicochemical properties upon the addition of the negatively charged sulfated groups
Based on their subcellular localization, sulfatases are grouped in two main categories: those expressed in lysosomes, that act at acidic pH and are involved in catabolism, and those present in the endoplasmic reticulum, Golgi apparatus and at the cell surface acting at neutral pH and more likely involved in biosynthetic, rather than catabolic, pathways [59]
The above synopsis highlights the complexity of skeletal defects caused by mutations in genes encoding for enzymes and transporters involved in sulfate metabolism
Summary
Sulfated compounds include a wide array of substances, ranging in molecular weight from less than 103 Da to greater than 106 Da, that undergo striking changes in their physicochemical properties upon the addition of the negatively charged sulfated groups. The highly acidic and hydrophilic properties of GAGs have a major influence on tissue hydration, elasticity, and cation composition They bind with high-affinity ECM proteins, growth factors, enzymes, and cell surface receptors [2,3,4]. Sulfation has a significant role in the biotransformation of many endogenous low-molecular-weight compounds including catecholamines and iodothyronines [8], cholesterol, bile acids, and steroids [9,10,11]. These examples highlight that proper sulfation of endogenous molecules is a widespread phenomenon so far poorly explored, it is essential for growth and development. This review deals with disorders of the biosynthesis of sulfated macromolecules, which are associated mainly with abnormal development of the skeleton
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