Aggrecan and extracellular matrix proteoglycans (ACAN)

Aggrecan (ACAN) is a large chondroitin sulfate proteoglycan that serves as a primary structural component of the extracellular matrix (ECM) in articular cartilage and intervertebral discs (UniProt: P16112) [1]. It functions by forming massive supramolecular aggregates through non-covalent interactions with hyaluronan and link proteins at specific protein-protein interfaces, providing the high fixed-charge density required for cartilage to resist compressive loads (NCBI Gene: 176) [2]. In pathological conditions such as osteoarthritis and degenerative disc disease, these interfaces are compromised by the action of aggrecanases, specifically ADAMTS-4 and ADAMTS-5, which cleave the aggrecan core protein and lead to matrix depletion (PMID: 30243897) [3]. Therapeutic interventions aim to stabilize these protein-protein interfaces or inhibit the proteolytic enzymes responsible for their degradation to preserve joint function (PMID: 28864355) [4]. Current drug development focuses on highly selective ADAMTS inhibitors and chondroprotective agents that maintain the integrity of the aggrecan-hyaluronan complex and other ECM proteoglycans like versican and decorin (PMID: 31540133) [5].

Other names

Cartilage-specific proteoglycan core proteinCSPCPChondroitin sulfate proteoglycan 1Large aggregating proteoglycanAcanVersicanDecorinBiglycan

Inhibition of proteolytic enzymes, specifically aggrecanases (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases (MMPs), to prevent the cleavage of the proteoglycan core protein at specific peptide bonds (e.g., Glu373-Ala374), thereby preserving the integrity of the protein-protein interfaces within the extracellular matrix (PMID: 30243897) [3].