Proteoglycans synthesized by human cartilage wore studied in explants and in chondrocyte cultures. The D1 fraction proteoglycans radiolabelled with 35SO4 were analyzed by 3-16% sodium dodecyl sulfate polyacrylamide gel electrophoresis or on 3-5% acrylamide gels. After 24 h in culture, osteoarthritic and age matched nonarthritic cartilage synthesized one aggrecan core protein (L(I)) whose apparent size after chondroitinase ABC/keratanase digestion was ~ 520 kDa. Three proteoglycan core proteins were found in the D1 fraction of the medium compartment of nonarthritic chondrocytes, whose apparent sizes were ~520 kDa (L(I)), ~390 kDa (L(II)), and ~480 kDa (L(III)). The L(II) and L(III) core proteins were routinely absent from osteoarthritic chondrocytes. Chondrocytes from a 28-year-old patient with osteoarthritis secondary to congenital hip dysplasia synthesized principally the L(I) proteoglycan core protein.
Aggrecan is synthesized and secreted continuously by chondrocytes, and it follows the same intracellular pathways of synthesis as other secretory proteins.
However, in later stages, aggrecan synthesis is decreased, ..
SOX9 is considered to be an early chondrogenicmarker that induces the synthesis of collagen II and aggrecan. Thepresent study further investigated whether ICA was able to promotethe expression of SOX9 and subsequently induce chondrogenesis. Asshown in , the TGF-β3+ ICA group exhibited more intense staining of SOX9 and anincreased percentage of positively stained cells (47.87±13.32%)compared with the TGF-β3 group (32.02±9.42%). Notably, the majorityof cells stained positively within the aggregates, while lessstaining was detected in the single cells, suggesting that it isnecessary for BMSCs undergoing chondrogenic induction to formaggregates and that ICA can induce the chondrogenesis.
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Although it is clear that many factors affect the synthesis of glycosaminoglycan chains and oligosaccharides, it is not yet fully understood how the composition of aggrecan relates to the age and site of the tissue or to the range of growth factors and cytokines acting on the chondrocytes in which it is expressed.
The 3 globular domains of the aggrecan protein contain sequences that are highly conserved amongst aggrecan from different vertebrate species, but the extended domains are less well conserved.
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One of the earliest features of the development of osteoarthritis is degeneration of the articulating surfaces of the joint. This is characterized by fibrillation of the articular cartilage, in which the mesh of collagen fibers is disrupted. Degeneration of type II collagen is seen, as well as a decrease in the extracellular matrix.22 Loss of proteoglycan from the matrix is characteristic. The loss of aggrecan, the predominant PRG in articular cartilage imposes an increasing load on the collagen fibrils, causing further breakdown.23 Early in the course of OA, the tissue mounts an attempt at repair. Chondrocytes proliferate and there is an increase in matrix synthesis.24 However, if this repair process is disrupted for any reason including the use of NSAIDs, degradative enzymes overwhelm the synthetic capability and the repair fails. Particular compositional, molecular, and structural changes will continue to occur within the articular cartilage including decreased proteoglycan and increased water content, collagen fibril network disorganization, and proteoglycan separation, as long as the inciting issue (NSAID use) continues. (See Figure 5.)