Anti-TNF-Alpha Therapy Enhances the Effects of Enzyme Replacement Therapy in Rats with Mucopolysaccharidosis Type VI

Eliyahu, Efrat; Wolfson, Theodore; Ge, Yi; Jepsen, Karl J.; Schuchman, Edward H.; Simonaro, Calogera M.

doi:10.1371/journal.pone.0022447

Cited by 56 publications

(67 citation statements)

References 29 publications

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“…However, there was no impact on bone growth or mobility since stored GAGs still remained in chondrocytes of the growth plate. The efficacy of ERT alone and combined treatment using ERT and anti-TNF-α drug (specific monoclonal antibody against TNF-α: CNTO1081) was also tested [37]. Both treatments markedly reduced serum levels of TNF-α and RANKL, although only the combined treatment reduced TNF-α in the articular cartilage.…”

Section: Anti-inflammatory Drugsmentioning

confidence: 99%

“…Only the combined therapy suppressed hyperplasia of synovial cells into underlying bone and clinical effects on other organs that are not accessible to the enzyme (e.g. cartilage) [37]. However, these therapies do have adverse effects.…”

Section: Anti-inflammatory Drugsmentioning

confidence: 99%

“…However, there was no impact on bone growth or mobility since stored GAGs still remained in chondrocytes of the growth plate. The efficacy of ERT alone and combined treatment using ERT and anti-inflammatory drug was also tested [37]. An anti-inflammatory treatment should be evaluated alone or in combined therapy with ERT, HSCT, or future gene therapy for MPSs [38,39].…”

Section: Introductionmentioning

confidence: 99%

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Therapies for the bone in mucopolysaccharidoses

Tomatsu

Barrera

Alméciga-Díaz

et al. 2015

Molecular Genetics and Metabolism

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Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required.Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life.This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.

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Section: Anti-inflammatory Drugsmentioning

confidence: 99%

Section: Anti-inflammatory Drugsmentioning

confidence: 99%

“…However, there was no impact on bone growth or mobility since stored GAGs still remained in chondrocytes of the growth plate. The efficacy of ERT alone and combined treatment using ERT and anti-inflammatory drug was also tested [37]. An anti-inflammatory treatment should be evaluated alone or in combined therapy with ERT, HSCT, or future gene therapy for MPSs [38,39].…”

Section: Introductionmentioning

confidence: 99%

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Therapies for the bone in mucopolysaccharidoses

Tomatsu

Barrera

Alméciga-Díaz

et al. 2015

Molecular Genetics and Metabolism

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“…GAGs and partially degraded fragments have previously been implicated as direct mediators of inflammation through activation of TLRs (34). Rodent models of lysosomal storage disease have been shown to exhibit less severe symptoms following the genetic removal of TLR4 or the pharmaceutical blockade of TNF-α signaling, consistent with an inflammatory component to disease pathogenesis (35,36). To determine whether GAG accumulation occurs during arthritis development in our GUSB-deficient strains, we performed Alcian blue staining to detect the presence of acidic polysaccharides, including GAGs, in joint histopathology sections at 4 weeks after infection.…”

Section: Figurementioning

confidence: 99%

Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity

Bramwell¹,

Ma²,

Weis³

et al. 2013

J. Clin. Invest.

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Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusb h . C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusb h allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs

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“…Clinical/observational biomarkers Hair morphology [56,57] Response to therapy Human Brain MRI images [58][59][60][61] Burden of disease (CNS) Response to therapy Human in fluids or tissues consist of a non-specific dye binding assay, simple chromatographic separation, or measurement of specific disaccharides after depolymerization of the GAGs. Importantly, none of these methods reflects the exact structure of the accumulated GAG chains.…”

Section: Primary Markersmentioning

confidence: 99%