Age-related Changes in the Response of Human Articular Cartilage to IL-1α and Transforming Growth Factor-β (TGF-β)

Abstract

Cartilage glycosaminoglycan (GAG) synthesis and composition, upon which its structural integrity depends, varies with age, is modified by anabolic and catabolic stimuli, and is regulated by UDP-glucuronate availability. However, how such stimuli, prototypically represented by transforming growth factor-␤1 (TGF-␤1) and IL-1␣, modify GAG synthesis during aging of normal human articular cartilage is not known. Using explants, we show that chondroitin sulfate (CS):total GAG ratios decrease, whereas C6S:C4S ratios increase with cartilage maturation, and that chondrocytes in the cartilage mid-zone, but not the superficial or deep zones, exhibit uridine 5-diphosphoglucose dehydrogenase (UDPGD) activity, which is also increased in mature cartilage. We also show that IL-1␣ treatment reduces both total GAG and CS synthesis, decreases C6S:C4S ratios (less C6S), but fails to modify chondrocyte UDPGD activity at all ages. On the other hand, TGF-␤1 increases total GAG synthesis in immature, but not mature, cartilage (stimulates CS but not non-CS), age-independently decreases C6S:C4S (more C4S), and increases chondrocyte UDPGD activity in a manner inversely correlated with age. Our findings show that TGF-␤1, but not IL-1␣, modifies matrix synthesis such that its composition more closely resembles "less mature" articular cartilage. These effects of TGF-␤1, which appear to be restricted to periods of skeletal immaturity, are closely associated although not necessarily mechanistically linked with increases in chondrocyte UD-PGD activity. The antianabolic effects of IL-1␣ are, on the other hand, likely to be independent of any direct modification in UDPGD activity and manifest equally in human cartilage of all ages.

Molecular Cloning and Characterization of UDP-glucose Dehydrogenase from the Amphibian Xenopus laevis and Its Involvement in Hyaluronan Synthesis

“…Although cytoplasmic UDP-sugar precursor concentrations could directly affect the activity of HA synthases located in the cell membrane, the UDP-sugar transporters would be saturated at the cellular concentration of the UDP-sugar precursors thereby maintaining constant concentrations inside the Golgi apparatus and thus the constant activity of the Golgi GAG synthetic enzymes. The tight relationship between UGDH activity and GAG synthesis was also recently outlined in in vivo experiments with fibroblast-like synovial lining cells (58) and in vitro on immature and mature human articular cartilage explants (59), although the key importance of UGDH activity in GAG production was already suggested years ago (60,61).…”

Aggrecan, aging and assembly in articular cartilage

“…Peptide fragments of link protein [162][163][164], G3 domain [165][166][167] and HA oligosaccharides have been reported to act in this manner [168][169][170][171]. This may explain, at least in part, the age-related decline that is observed in the response of chondrocytes to growth factors [172,173]. The consequence of the alterations in the sulphation pattern of CS remains unclear, but by inference may reflect important but as yet poorly understood changes in the properties of the ECM.…”

Cartilage tissue engineering for degenerative joint disease☆

“…) is altered [33][34][35]. In OA cartilage, expression of β-galactosidase was increased close to but not away from the OA damage sites suggesting that cell senescence plays a role in the progression of aging cartilage towards disease [36].…”