Articular chondrocytes from animals with a dermatan sulfate storage disease undergo a high rate of apoptosis and release nitric oxide and inflammatory cytokines: A possible mechanism underlying degenerative joint disease in the mucopolysaccharidoses
Cm. Simonaro et al., Articular chondrocytes from animals with a dermatan sulfate storage disease undergo a high rate of apoptosis and release nitric oxide and inflammatory cytokines: A possible mechanism underlying degenerative joint disease in the mucopolysaccharidoses, LAB INV, 81(9), 2001, pp. 1319-1328
Mucopolysaccharidosis (MPS) Type VI (Maroteaux-Lamy Disease) is the lysosom
al storage disease characterized by deficient arylsulfatase B activity and
the resultant accumulation of dermatan sulfate-containing glycosaminoglycan
s (GAGs). A major feature of this and other MPS disorders is abnormal carti
lage and bone development leading to short stature, dysostosis multiplex, a
nd degenerative joint disease. To investigate the underlying cause(s) of de
generative joint disease in the MPS disorders, articular cartilage and cult
ured articular chondrocytes were examined from rats and cats with MPS VI. A
n age-progressive increase in the number of apoptotic chondrocytes was iden
tified in the MPS animals by terminal transferase nick-end translation (TUN
EL) staining and by immunohistochemical staining with anti-poly (ADP-ribose
) polymerase (PARP) antibodies. Articular chondrocytes grown from these ani
mals also released more nitric oxide (NO) and tumor necrosis factor alpha (
TNF-a) into the culture media than did control chondrocytes. Notably, derma
tan sulfate, the GAG that accumulates in MPS VI cells, induced NO release f
rom normal chondrocytes, suggesting that GAG accumulation was responsible,
in part, for the enhanced cell death in the MPS cells. Coculture of normal
chondrocytes with MPS VI cells reduced the amount of NO release, presumably
because of the release of arylsulfatase B by the normal cells and reuptake
by the mutant cells. As a result of the enhanced chondrocyte death, marked
proteoglycan and collagen depletion was observed in the MPS articular cart
ilage matrix. These results demonstrate that MPS VI articular chondrocytes
undergo cell death at a higher rate than normal cells, because of either in
creased levels of dermatan sulfate and/or the presence of inflammatory cyto
kines in the MPS joints. In turn, this leads to abnormal cartilage matrix h
omeostasis in the MPS individuals, which further exacerbates the joint defo
rmities characteristic of these disorders.