Aggrecan and Hyaluronan: The Infamous Cartilage Polyelectrolytes – Then and Now

Abstract

Cartilages are unique in the family of connective tissues in that they contain a high concentration of the glycosaminoglycans, chondroitinsulfate and keratan sulfate attached to the core protein of the proteoglycan, aggrecan. 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 during 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 the development of joint disease. In addition, we describe the pathways for hyaluronan metabolism, with particular focus on the role as a “metabolicrheostat” during chondrocyte responses in cartilage remodeling in growth and disease.Future advances in effective therapeutic targeting of cartilage loss during osteoarthritic diseases of the joint as an organ as well as in cartilage tissue engineering would benefit from ‘big data’ 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.

ADAMTS4 is a crucial proteolytic enzyme for versican cleavage in the amnion at parturition

“…The hyalectan family is comprised of VCAN, ACAN, BCAN and NCAN 13 . Unlike the dominant presence of ACAN in the cartilaginous tissue 58 , and NCAN and BCAN in the matrix of the central nervous system 59 , 60 , we found VCAN rather than other family members was the dominant hyalectan in the amnion, which appears to be consistent with the wide distribution of VCAN in the developing embryo 19 . VCAN is present in multiple isoforms, which share a homologous globular N-, C-terminal, and a central glycosaminoglycan (GAG) binding domain, but vary in size and the number of GAG chains.…”

A Review of Cyclic Phosphatidic Acid and Other Potential Therapeutic Targets for Treating Osteoarthritis

“…CHSY2 plays a role in the sulfation process and contributes to the addition of sulfate groups to CS chains. CHSY2 may have distinct substrate preferences or enzymatic activities compared with CHSY1 [59]. CHSY3 is the third isoform in this enzyme family.…”

“…Similar to CHSY1 and CHSY2, it participates in the sulfation of CS chains by adding sulfate groups to specific positions in the core protein structure [60,61]. CHSY3 may have unique characteristics and functions in the CS biosynthesis pathway [59]. These isoforms are collectively responsible for the sulfation pattern of CS molecules, which varies depending on the tissue and specific functions within the body [59].…”

“…CHSY3 may have unique characteristics and functions in the CS biosynthesis pathway [59]. These isoforms are collectively responsible for the sulfation pattern of CS molecules, which varies depending on the tissue and specific functions within the body [59]. Understanding the functions of CHSY1, CHSY2, and CHSY3 is crucial for unraveling the complexity of CS biosynthesis and its implications in tissue health and various diseases, including those related to connective tissues and joints.…”

Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis

“…Therefore, exogenous HA-based hydrogels (i.e., polymeric network dissolved/dispersed in an aqueous solvent) have been extensively investigated as optimal synthetic SF substitutes designed for pain reduction and enhanced mobility recovery. Based on clinical reports of progressive physiological HA functional degradation and molecular weight (MW) distribution shifts in ageing patients, many therapeutic HA-based injectables for mild to moderate knee OA were developed using high-MW linear polymers of various origins [ 13 , 14 ]. However, the available aggregated clinical evidence suggested an absence of significant efficacy of classical HA-based viscosupplementation products in OA [ 15 , 16 , 17 , 18 ].…”