Enhanced chondrocyte apoptosis leads to abnormal cartilage in rats and cats with glycosaminoglycan storage diseases

Abstract

The mucopolysaccharidoses (MPS) are a family of glycosaminoglycan (GAG) storage diseases caused by the deficient activities of specific lysosomal enzymes. A major feature of the MPS disorders is abnormal cartilage and bone development leading to short stature, dysostosis multiplex, and degenerative joint disease. Ultrastructurally, the cytoplasm of affected MPS chondrocytes is filled with membrane bound vacuoles containing undegraded GAGs. Clusters of hypertrophic chondrocytes form in these disorders, leading to the disruption of the normal cartilage organization. To further investigate the cellular pathology of the MPS disorders, primary cultured chondrocytes and articular cartilage were examined from cats and rats with MPS typeVI (Maroteaux-Lamy disease). Markedly increased numbers of apoptotic chondrocytes were identified by TUNEL staining and immunohistochemically with anti-poly (ADP-ribose) polymerase antibodies in the MPS animals as compared to age-matched controls. The prevalence of apoptotic cells was correlated with increased levels of nitrite and tumor necrosis factor-α. Marked proteoglycan depletion also was observed in the MPS epiphyses by Safranin-O staining, and the presence of excess collagen type II was detected by immunostaining. A model of MPS endochondryl bone pathology is proposed in which an inflammatory response to mechanical trauma is caused by the deformed and irregular subchondral bone contours, leading to increased nitric oxide (NO) production in response to TNF-α, thereby inducing chondrocyte cell death. Novel treatment strategies for these disorders might, therefore, be considered to prevent inflammation or inhibit NO production as an alternative to providing the missing enzymatic activities.