Proteoglycan 4 (PRG4) is a macromolecule synthesized and found within the synovial joint that contributes lubricating and other functions to maintain joint health. PRG4 secretion by articular cartilage is an important parameter of PRG4 mass balance in the synovial joint and is influenced in vitro by a number of chemical and mechanical mediators. With joint aging and osteoarthritis (OA), cartilage PRG4 secretion may be altered due to changes in constitutive and induced chondrocyte expression and changes in SF regulation of cartilage. The overall motivation of this dissertation was to contribute to an understanding of the changes in regulation of articular cartilage PRG4 secretion by TGF-β1, a potent stimulus, and by human synovial fluid (hSF), a complex mixture that interacts with cartilage physiologically, with aging and OA.
In normal human articular cartilage, constitutive and TGF-β1-stimulated PRG4 production decreased with increasing age, and these age-dependent declines were associated with decreases with age in the number of PRG4+ chondrocytes without a marked alteration in the density of chondrocytes in the superficial zone. Changes in activity and responsiveness of chondrocytes likely underlie age-related declines in PRG4 production. Age-associated decrease in cartilage constitutive and TGF-β1-stimulated PRG4 production may be related to the age-associated predisposition to cartilage degeneration and OA. hSF contains endogenous regulators of cartilage PRG4 secretion, resulting in a net stimulation. Cartilage PRG4 secretion was substantially stimulated by hSF from OA patients (OA-hSF), compared to hSF from normal cadaveric donors (NL-hSF) and pooled human serum (HS) from normal adult donors. OA-hSF stimulation of cartilage PRG4 secretion was not substantially modulated by inhibition of the TGF-β, IL-1, and/or TNF signaling pathways, individually.
Elucidating the age- and OA- related changes in cartilage PRG4 secretion, due to alterations in constitutive and induced chondrocyte expression and alterations in hSF regulation of cartilage, is one step towards a systems-based understanding of synovial joint PRG4 homeostasis and derangement in health, aging, and disease.