Joint and bone disease in mucopolysaccharidoses VI and VII: identification of new therapeutic targets and biomarkers using animal models.
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.
Simonaro
Calogera M
CM
Department of Human Genetics, Mount Sainai School of Medicine, New York, NY 10029, USA. Calogera.Simonaro@mssm.edu
D'Angelo
Marina
M
Haskins
Mark E
ME
Schuchman
Edward H
EH
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism*; D001847:Bone Diseases / Q000150:complications*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002415:Cats; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D007118:Immunoassay; D007150:Immunohistochemistry; D007249:Inflammation; D007592:Joint Diseases / Q000150:complications*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009087:Mucopolysaccharidosis VI / Q000150:complications / Q000175:diagnosis* / Q000628:therapy*; D016538:Mucopolysaccharidosis VII / Q000150:complications / Q000175:diagnosis* / Q000628:therapy*; D009569:Nitric Oxide / Q000378:metabolism; D015676:Osteonectin / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013977:Tibia / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism
D000963:Antimetabolites; D015415:Biomarkers; D016207:Cytokines; D015676:Osteonectin; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D001973:Bromodeoxyuridine