| Aggrecan is a lectican-family chondroitin sulfate proteoglycan that forms a principal structural and functional component of cartilage extracellular matrix, where it supports skeletal development, load-bearing capacity, and maintenance of joint and spine architecture by organizing hydrated macromolecular assemblies in concert with collagen and other matrix proteins. The core protein contains three globular domains and intervening glycosaminoglycan-attachment regions; the N-terminal G1 domain binds hyaluronan and link protein to generate large, multivalent proteoglycan aggregates, while the glycosaminoglycan-rich domains carry dense chondroitin sulfate and keratan sulfate chains that create a highly charged, osmotically active network able to attract water and resist compressive forces, and the C-terminal domain contributes to matrix organization and secretion efficiency. Aggrecan operates within a matrix-signaling environment in which its interactions with hyaluronan and link protein stabilize pericellular and interterritorial matrix structures around chondrocytes, shape the mechanical microenvironment that influences chondrocyte metabolic activity, and integrate with collagen type II fibrils to define tissue stiffness and resilience under repetitive mechanical loading. The balance between aggrecan synthesis and its cleavage by matrix metalloproteinases and ADAMTS-family aggrecanases controls the integrity of this network; proteolytic events at defined sites within the core protein disassemble aggregates, diminish fixed charge density, and reduce the capacity of cartilage to maintain swelling pressure, which alters joint biomechanics and predisposes to further matrix damage. Aggrecan expression and domain organization also participate in developmental programs of cartilage and growth plate maturation, where the regulated presence of the hyaluronan-binding and glycosaminoglycan-bearing regions aligns with chondrocyte proliferation and hypertrophy and contributes to proper skeletal patterning. In osteoarthritic cartilage, depletion of aggrecan from the matrix and accumulation of its fragments in synovial fluid associate with early stages of tissue degeneration, and elevated aggrecanase and metalloproteinase activity links inflammatory mediators and mechanical overloading to progressive matrix loss; at the same time, aggrecan production remains a key feature of reparative responses, including cell-based cartilage repair strategies that depend on restoration of a dense proteoglycan network to recover normal tissue function. |
