aggrecan

Aggrecan is a large, secreted proteoglycan that is a major constituent of the extracellular matrix in articular cartilage and other cartilaginous tissues, including the intervertebral disc. It forms proteoglycan aggregates with hyaluronic acid and the link protein, producing a highly hydrated network that helps cartilage resist compressive forces and maintain its shape.

Molecularly, aggrecan consists of a central core protein to which dense arrays of glycosaminoglycan chains are covalently attached. The core protein contains three globular domains: G1 at the N-terminus, G2 in the middle, and G3 at the C-terminus. The G1 domain binds hyaluronan in the presence of link protein, anchoring the proteoglycan to the hyaluronan backbone; the G3 domain contains a lectin-like region and other motifs involved in matrix interactions. The proteoglycan is heavily substituted with sulfated glycosaminoglycan chains, mainly chondroitin sulfate and keratan sulfate, which provide negative charge and high hydration.

Functionally, aggrecan provides osmotic swelling pressure within cartilage, enabling it to resist compressive loads during joint movement. It interacts with collagen II and other matrix components to help organize the extracellular matrix and retain water. Its highly charged GAG chains also serve as reservoirs for signaling molecules, influencing cartilage development and repair.

Genetically, aggrecan is encoded by the ACAN gene. Mutations in ACAN are linked to a spectrum of skeletal growth disorders, including spondyloepimetaphyseal dysplasias and familial osteochondritis dissecans, as well as short stature associated with advanced bone age. Regulation of aggrecan turnover and processing is an area of active study in cartilage biology and osteoarthritis research.