transforming-growth-factor-beta and Mucopolysaccharidosis-VI

The mucopolysaccharidoses (MPS) are inherited metabolic disorders resulting from the defective catabolism of glycosaminoglycans. In this report, we find that the stimulation of MPS connective tissue cells by the inflammatory cytokines causes enhanced secretion of several matrix-degrading metalloproteinases (MMPs). In addition, expression of tissue inhibitor of metalloproteinase-1 was elevated, consistent with the enhanced MMP activity. These findings were not restricted to one particular MPS disorder or species, and are consistent with previous observations in animal models with chemically induced arthritis. Bromodeoxyuridine incorporation studies also revealed that MPS chondrocytes proliferated up to 5-fold faster than normal chondrocytes, and released elevated levels of transforming growth factor-beta, presumably to counteract the marked chondrocyte apoptosis and matrix degradation associated with MMP expression. Despite this compensatory mechanism, studies of endochondral ossification revealed a reduction in chondro-differentiation in the growth plates. Thus, although MPS chondrocytes grew faster, most of the newly formed cells were immature and could not mineralize into bone. Our studies suggest that altered MMP expression, most likely stimulated by inflammatory cytokines and nitric oxide, is an important feature of the MPS disorders. These data also identify several proinflammatory cytokines, nitric oxide, and MMPs as novel therapeutic targets and/or biomarkers of MPS joint and bone disease. This information should aid in the evaluation of existing therapies for these disorders, such as enzyme replacement therapy and bone marrow transplantation, and may lead to the development of new therapeutic approaches.

Topics: Animals; Antimetabolites; Apoptosis; Biomarkers; Bone Diseases; Bromodeoxyuridine; Cats; Cell Proliferation; Cells, Cultured; Chondrocytes; Cytokines; Disease Models, Animal; Dogs; Immunoassay; Immunohistochemistry; Inflammation; Joint Diseases; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Nitric Oxide; Osteonectin; Rats; Reverse Transcriptase Polymerase Chain Reaction; Tibia; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

To carry out a detailed morphological study of the cornea of a 16 year old female with a Maroteaux-Lamy syndrome (MLS).. Following a penetrating keratoplasty in July 1999, ultrastructural changes in the cornea were examined using electron microscopy. Proteoglycans were visualised using cuprolinic blue dye; and betaig-h3 and keratan sulphate were detected by immunoelectron microscopy.. The epithelial cells were degenerate and contained apoptotic nuclei. Proteoglycans were present in epithelial cells, intercellular spaces, and in swollen desmosomes. An abnormally large quantity of proteoglycans was present throughout the stroma. Keratocytes throughout the stroma had no cell organelles, were vacuolated, and contained a large quantity of abnormal proteoglycans. Labelling for betaig-h3 was intense around electron lucent spaces in stroma. No labelling was seen in keratocytes or endothelial cells. In normal cornea, keratan sulphate labelling was regular throughout the stroma. In MLS VI type B cornea, keratan sulphate labelling was weak in the anterior stroma but very intense in the posterior stroma and in keratocyte lysosomes and vacuoles.. A deficiency of aryl sulfatase B results in the deposition of keratan sulphate proteoglycan and other proteoglycans in lysosomes, causing the death of keratocytes and an abnormal build-up of proteoglycans in the stroma. This might be responsible for the lateral aggregation of collagen fibrils and impaired fibrillogenesis in MLS VI. Degenerate swollen keratocytes, together with gross changes in epithelial, stromal, and endothelial cells, would be expected to increase light scattering significantly in these corneas.

Topics: Adolescent; Cornea; Extracellular Matrix Proteins; Female; Humans; Keratan Sulfate; Microscopy, Electron; Mucopolysaccharidosis VI; Neoplasm Proteins; Transforming Growth Factor beta