RGD Reference Report - Anti-TNF-alpha therapy enhances the effects of enzyme replacement therapy in rats with mucopolysaccharidosis type VI. - Rat Genome Database

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Anti-TNF-alpha therapy enhances the effects of enzyme replacement therapy in rats with mucopolysaccharidosis type VI.

Authors: Eliyahu, Efrat  Wolfson, Theodore  Ge, Yi  Jepsen, Karl J  Schuchman, Edward H  Simonaro, Calogera M 
Citation: Eliyahu E, etal., PLoS One. 2011;6(8):e22447. doi: 10.1371/journal.pone.0022447. Epub 2011 Aug 22.
RGD ID: 39131283
Pubmed: PMID:21887218   (View Abstract at PubMed)
PMCID: PMC3159569   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0022447   (Journal Full-text)


BACKGROUND: Although enzyme replacement therapy (ERT) is available for several lysosomal storage disorders, the benefit of this treatment to the skeletal system is very limited. Our previous work has shown the importance of the Toll-like receptor 4/TNF-alpha inflammatory pathway in the skeletal pathology of the mucopolysaccharidoses (MPS), and we therefore undertook a study to examine the additive benefit of combining anti-TNF-alpha therapy with ERT in a rat model of MPS type VI.
METHODOLOGY/PRINCIPAL FINDINGS: MPS VI rats were treated for 8 months with Naglazyme® (recombinant human N-acetyl-galactosamine-4-sulfatase), or by a combined protocol using Naglazyme® and the rat-specific anti-TNF-alpha drug, CNTO1081. Both protocols led to markedly reduced serum levels of TNF-alpha and RANKL, although only the combined treatment reduced TNF-alpha in the articular cartilage. Analysis of cultured articular chondrocytes showed that the combination therapy also restored collagen IIA1 expression, and reduced expression of the apoptotic marker, PARP. Motor activity and mobility were improved by ERT, and these were significantly enhanced by combination treatment. Tracheal deformities in the MPS VI animals were only improved by combination therapy, and there was a modest improvement in bone length. Ceramide levels in the trachea also were markedly reduced. MicroCT analysis did not demonstrate any significant positive effects on bone microarchitecture from either treatment, nor was there histological improvement in the bone growth plates.
CONCLUSIONS/SIGNIFICANCE: The results demonstrate that combining ERT with anti-TNF-alpha therapy improved the treatment outcome and led to significant clinical benefit. They also further validate the usefulness of TNF-alpha, RANKL and other inflammatory molecules as biomarkers for the MPS disorders. Further evaluation of this combination approach in other MPS animal models and patients is warranted.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ArsbRatabnormal bone trabecula morphology  IAGP  RGD 
ArsbRatabnormal synovial joint membrane morphology  IAGP  RGD 
MPR/IarRatabnormal synovial joint membrane morphology  IAGP compared to normal and treatedRGD 
ArsbRatabnormal tibiofemoral joint morphology  IAGP  RGD 
MPR/IarRatabnormal tibiofemoral joint morphology  IAGP compared to normal and treatedRGD 
ArsbRatabnormal trabecular bone morphology  IAGP  RGD 
MPR/IarRatabnormal trabecular bone morphology  IAGP compared to normal and treatedRGD 
ArsbRatabnormal trachea morphology  IAGP  RGD 
MPR/IarRatabnormal trachea morphology  IAGP compared to normal and treatedRGD 
ArsbRatimpaired coordination  IAGP  RGD 
MPR/IarRatimpaired coordination  IAGP compared to treatedRGD 
ArsbRatimpaired limb coordination  IAGP  RGD 
MPR/IarRatimpaired limb coordination  IAGP compared to treatedRGD 
ArsbRatincreased circulating tumor necrosis factor level  IAGP  RGD 
MPR/IarRatincreased circulating tumor necrosis factor level  IAGP compared to normal and treatedRGD 
ArsbRattrachea inflammation  IAGP  RGD 
MPR/IarRattrachea inflammation  IAGP compared to treatedRGD 
Objects Annotated

Genes (Rattus norvegicus)
Arsb  (arylsulfatase B)
Tnf  (tumor necrosis factor)
Tnfsf11  (TNF superfamily member 11)

Genes (Mus musculus)
Arsb  (arylsulfatase B)
Tnf  (tumor necrosis factor)
Tnfsf11  (tumor necrosis factor (ligand) superfamily, member 11)

Genes (Homo sapiens)
ARSB  (arylsulfatase B)
TNF  (tumor necrosis factor)
TNFSF11  (TNF superfamily member 11)

Strains
MPR/Iar  (NA)


Additional Information