title: Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII.
abstract: Mucopolysaccharidosis type VII (MPS VII) is characterized by deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan and dermatan sulfate glycosaminoglycans (GAGs), and multisystemic disease. MPS VII patients can develop kypho-scoliotic deformity and spinal cord compression due to disease of intervertebral disks, vertebral bodies, and associated tissues. We have previously demonstrated in MPS VII dogs that intervertebral disks degenerate, vertebral bodies have irregular surfaces, and vertebral body epiphyses have reduced calcification, but the pathophysiological mechanisms underlying these changes are unclear. We hypothesized that some of these manifestations could be due to upregulation of destructive proteases, possibly via the binding of GAGs to Toll-like receptor 4 (TLR4), as has been proposed for other tissues in MPS models. In this study, the annulus fibrosus of the intervertebral disk of 6-month-old MPS VII dogs had cathepsin B and K activities that were 117- and 2-fold normal, respectively, which were associated with elevations in mRNA levels for these cathepsins as well as TLR4. The epiphyses of MPS VII dogs had a marked elevation in mRNA for the cartilage-associated gene collagen II, consistent with a developmental delay in the conversion of the cartilage to bone in this region. The spine obtained at autopsy from a young man with MPS VII exhibited similar increased cartilage in the vertebral bodies adjacent to the end plates, disorganization of the intervertebral disks, and irregular vertebral end plate morphology. These data suggest that the pathogenesis of destructive changes in the spine in MPS VII may involve upregulation of cathepsins. Inhibition of destructive proteases, such as cathepsins, might reduce spine disease in patients with MPS VII or related disorders.
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. lachlans@mail.med.upenn.edu
authors.forename: Lachlan J
authors.initials: LJ
authors.lastname: Smith
authors.forename: Guilherme
authors.initials: G
authors.lastname: Baldo
authors.forename: Susan
authors.initials: S
authors.lastname: Wu
authors.forename: Yuli
authors.initials: Y
authors.lastname: Liu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Elliott
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Ponder
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D016538:Mucopolysaccharidosis VII / Q000150:complications*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D013122:Spinal Diseases / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D002403:Cathepsins; D020782:Matrix Metalloproteinases