Control of tissue homeostasis by the extracellular matrix: Synthetic heparan sulfate as a promising therapeutic for periodontal health and bone regeneration

Abstract

Proteoglycans are core proteins associated with carbohydrate/sugar moieties that are highly variable in disaccharide composition, which dictates their function. These carbohydrates are named glycosaminoglycans, and they can be attached to proteoglycans or found free in tissues or on cell surfaces. Glycosaminoglycans such as hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, and heparin/heparan sulfate have multiple functions including involvement in inflammation, immunity and connective tissue structure, and integrity. Heparan sulfate is a highly sulfated polysaccharide that is abundant in the periodontium including alveolar bone. Recent evidence supports the contention that heparan sulfate is an important player in modulating interactions between damage associated molecular patterns and inflammatory receptors expressed by various cell types. The structure of heparan sulfate is reported to dictate its function, thus, the utilization of a homogenous and structurally defined heparan sulfate polysaccharide for modulation of cell function offers therapeutic potential. Recently, a chemoenzymatic approach was developed to allow production of many structurally defined heparan sulfate carbohydrates. These oligosaccharides have been studied in various pathological inflammatory conditions to better understand their function and their potential application in promoting tissue homeostasis. We have observed that specific size and sulfation patterns can modulate inflammation and promote tissue maintenance including an anabolic effect in alveolar bone. Thus, new evidence provides a strong impetus to explore heparan sulfate as a potential novel therapeutic agent to treat periodontitis, support alveolar bone maintenance, and promote bone formation.

The Essential Role of Proteoglycans and Glycosaminoglycans in Odontogenesis

“…The most abundant proteoglycans in the periodontal tissue belong to a unique family of small leucine-rich repeat proteoglycans (SLRPs), including fibromodulin, biglycan, decorin, lumican, asporin, and osteoadherin. SLRPs are characterized by their leucine-rich repeats, which impart the ability to bind collagen and regulate collagen fibril growth and fibrillogenesis (Miguez et al 2023). Knockout animals with single or double SLRPs exhibit abnormalities in the PDL to different extents (Matheson et al 2005) (Table 3).…”

“…Proteoglycans, such as versican, biglycan, and syndecans, are found in the cementum (Miguez et al 2023). Versican is a crucial component of the ECM that forms highly hydrated complexes with hyaluronan and plays an important role in embryonic development (Nandadasa et al 2021).…”

“…Proteoglycans are also involved in the development and homeostasis of periodontium. Previous reviews have discussed their distribution and regulatory roles under pathological conditions (Chen et al 2021; Miguez et al 2023). Periodontal tissue development is a complex process that involves the cementum, gingiva, periodontal ligament (PDL), and alveolar bone.…”