Anti-TNF-Alpha Therapy Enhances the Effects of Enzyme Replacement Therapy in Rats with Mucopolysaccharidosis Type VI
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{"title"=>"Anti-TNF-alpha therapy enhances the effects of enzyme replacement therapy in rats with mucopolysaccharidosis type VI", "type"=>"journal", "authors"=>[{"first_name"=>"Efrat", "last_name"=>"Eliyahu", "scopus_author_id"=>"6508320837"}, {"first_name"=>"Theodore", "last_name"=>"Wolfson", "scopus_author_id"=>"55627302100"}, {"first_name"=>"Yi", "last_name"=>"Ge", "scopus_author_id"=>"36016440100"}, {"first_name"=>"Karl J.", "last_name"=>"Jepsen", "scopus_author_id"=>"7004821945"}, {"first_name"=>"Edward H.", "last_name"=>"Schuchman", "scopus_author_id"=>"7004364820"}, {"first_name"=>"Calogera M.", "last_name"=>"Simonaro", "scopus_author_id"=>"6602972154"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pui"=>"362390079", "sgr"=>"80051940065", "doi"=>"10.1371/journal.pone.0022447", "scopus"=>"2-s2.0-80051940065", "pmid"=>"21887218"}, "id"=>"710b536b-e727-3b6c-944a-52742e37157e", "abstract"=>"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.\\n\\nMETHODOLOGY/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.\\n\\nCONCLUSIONS/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.", "link"=>"http://www.mendeley.com/research/antitnfalpha-therapy-enhances-effects-enzyme-replacement-therapy-rats-mucopolysaccharidosis-type-vi", "reader_count"=>19, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>4, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>4, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>9, "Agricultural and Biological Sciences"=>4, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Brazil"=>1, "United Kingdom"=>1}, "group_count"=>3}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/743635"], "description"=>"<p>(<b>A</b>) MPS VI rats were subjected to the ERT (black) or combined ERT/anti-TNF-alpha (gray) treatment for 8 months, as described in the text (n = 8/group). The animals were euthanized 2 days after the last injection and serum was collected. Age-matched (37 weeks) normal (light gray) and untreated MPS VI (white) sera also were collected, and TNF-alpha and RANKL levels were determined using immunoassay kits (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0022447#s2\" target=\"_blank\">Materials and Methods</a>). As previously shown, untreated MPS VI animals had markedly elevated levels of these two inflammatory markers, and both were significantly reduced by either ERT or combined treatment (*p<0.005). No significant differences were observed between the two treatment protocols. (<b>B</b>) Untreated MPS VI rats exhibited markedly elevated TNF-alpha immunostaining (red) in the articular cartilage as compared to normal animals, which was modestly reduced by ERT and normalized by combined treatment. (<b>C</b>) Hyperplastic synovial membranes (*) with the formation of villi (SV), and invasion of the synovium into the subchondral bone (arrowhead, SB) was evident in untreated MPS VI and ERT-treated synovium. Animals treated with combined therapy exhibited markedly less joint inflammation, although the storage cells were still present.</p>", "links"=>[], "tags"=>["ert", "mps", "vi"], "article_id"=>414000, "categories"=>["Physiology", "Genetics", "Microbiology", "Immunology"], "users"=>["Efrat Eliyahu", "Theodore Wolfson", "Yi Ge", "Karl J. Jepsen", "Edward H. Schuchman", "Calogera M. Simonaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022447.g001", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_inflammatory_effects_of_ERT_and_combined_ERT_anti_TNF_alpha_therapy_in_MPS_VI_rats_/414000", "title"=>"Anti-inflammatory effects of ERT and combined ERT/anti-TNF-alpha therapy in MPS VI rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 15:30:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/744050"], "description"=>"<p>(<b>A</b>) Tracheas were collected from treated and untreated MPS VI and normal animals at the end of the study (37 weeks of age). As illustrated by this representative figure, untreated MPS VI rats had markedly thickened and abnormal, collapsed tracheas with narrow, flattened interior openings. These abnormalities were not altered by ERT, but were clearly improved by the combined treatment which resulted in rounded tracheas with almost statistically normalized cross sectional areas. (<b>B</b>) Immunohistochemical analysis of the tracheas showed increased expression of the pro-inflammatory and pro-apoptotic sphingolipid, ceramide, in the epithelial cells of untreated and ERT-treated animals (red), consistent with the occurrence of inflammatory disease. Tracheas from the combined treatment group showed almost normal ceramide expression.</p>", "links"=>[], "tags"=>["defects", "untreated", "treated", "mps", "vi"], "article_id"=>414424, "categories"=>["Physiology", "Genetics", "Microbiology", "Immunology"], "users"=>["Efrat Eliyahu", "Theodore Wolfson", "Yi Ge", "Karl J. Jepsen", "Edward H. Schuchman", "Calogera M. Simonaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022447.g004", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tracheal_defects_in_untreated_and_treated_MPS_VI_rats_/414424", "title"=>"Tracheal defects in untreated and treated MPS VI rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 15:33:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/743914"], "description"=>"<p>(<b>A</b>) MPS VI rats were subjected to the ERT (black) or combined ERT/anti-TNF-alpha (gray) treatment for 8 months, as described in the text (n = 8/group). The animals were euthanized 2 days after the last injection, and the femora and tibia were collected for microCT analysis. The results were compared to untreated age and gender-matched MPS VI rats (white), and the values expressed as a percentage of normal controls. ERT did not increase the length of the femora or tibia, while the combined protocol led to increases of ∼6 and 14%, respectively. Of note, the tibia and femora in the combined treatment group were on average ∼88 and 84% of normal, compared to 74 and 77% in the untreated MPS VI group. (<b>B</b>) microCT analysis of the coronal views. In untreated and treated MPS VI rats the trabecular density within the metaphyseal bone was reduced, the physeal growth plate was dysmorphic and disrupted, and the epiphyseal trabeculae were disorganized relative to the normal femora. Mild improvement from the combined treatment was detected. (<b>C</b>) microCT analysis of the mid-diaphyseal region of the femora showing axial views with subcortical trabecular infiltration into the marrow space. Although some reductions in trabecular infiltration were noted following treatment, these could not be confirmed by quantitative measures.</p>", "links"=>[], "tags"=>["microarchitecture", "untreated", "treated", "mps", "vi"], "article_id"=>414283, "categories"=>["Physiology", "Genetics", "Microbiology", "Immunology"], "users"=>["Efrat Eliyahu", "Theodore Wolfson", "Yi Ge", "Karl J. Jepsen", "Edward H. Schuchman", "Calogera M. Simonaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022447.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bone_length_and_microarchitecture_in_untreated_and_treated_MPS_VI_rats_/414283", "title"=>"Bone length and microarchitecture in untreated and treated MPS VI rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 15:32:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/743794"], "description"=>"<p>(<b>A</b>) MPS VI rats were subjected to ERT (boxes) or combined ERT/anti-TNF-alpha (circles) treatment for 8 months, as described in the text (n = 8/group). Two days after the last injection they were subjected to accelerating rotarod analysis at three different speeds, and their performance was compared to untreated, age and gender-matched MPS VI animals (triangles). At 10 RPM both groups of treated rats remained on the rotating rod for the maximal time (180 seconds), significantly longer than untreated animals (p<0.005). This trend became more pronounced at higher speeds, and there was also a significant distinction between the ERT and combined groups (p*<0.005). The times for individual animals are plotted, and the mean value for each group is indicated by the horizontal lines. (<b>B</b>) After treatment the animals also were subjected to gait analysis, as described in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0022447#s2\" target=\"_blank\">Materials and Methods</a>. Two different colors of food coloring were used to mark the front and hind paws of rats walking through a tube, and the distances between steps and angles of the steps were measured from the paw prints. Each rat was tested at least three times, and a summary of the average paw print values are shown in this figure. As can be seen, the angle of rear paw movement was reduced from 60° (untreated) to 45° (compared to untreated p = 0.004) and 30° (compared to untreated p = 0.0001) for the ERT and combined treatment animals, respectively. In addition, the distance the animals could move their front paws in each step was increased from 2.8 cm (untreated) to 4.2 cm and significantly to 5.1 cm in the combined treatment group (p = 0.03). The distance the animals moved their rear paws were not changed in the ERT group, and only modestly increased in the combined group (from 4.9 to 5.1 cm).</p>", "links"=>[], "tags"=>["gait", "untreated", "treated", "mps", "vi"], "article_id"=>414165, "categories"=>["Physiology", "Genetics", "Microbiology", "Immunology"], "users"=>["Efrat Eliyahu", "Theodore Wolfson", "Yi Ge", "Karl J. Jepsen", "Edward H. Schuchman", "Calogera M. Simonaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022447.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Motor_activity_and_gait_analysis_in_untreated_and_treated_MPS_VI_rats_/414165", "title"=>"Motor activity and gait analysis in untreated and treated MPS VI rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 15:31:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/744188"], "description"=>"<p>(<b>A</b>) MPS VI rats were subjected to the ERT or combined ERT/anti-TNF-alpha treatment for 8 months, as described in the text (n = 8/group). The animals were euthanized 2 days after the last injection, and articular chondrocytes were isolated and processed for western blotting. As shown in this representative experiment, ERT alone increased expression of collagen X, and to a more modest degree collagen IIA1. Similar observations were seen in the combined treatment group, except that the levels of collagen IIA1 expression were even more pronounced. To confirm these observations, immunofluorescent microscopic analysis of collagen IIA1 was carried out on articular cartilage sections from untreated, ERT-treated, and combined treatment animals (<b>B</b>). As evident in this figure, higher collagen IIA1 expression (red) was present in the combined treatment group, similar to normal. The expression of the apoptosis marker, PARP, also was examined in the treated and control animals by western blotting, and was only reduced by combined treatment. This is consistent with our previous work showing that anti-TNF-alpha therapy reduced TUNEL staining in articular chondrocytes of the MPS VI rats <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0022447#pone.0022447-Simonaro5\" target=\"_blank\">[18]</a>. In addition, the levels of the aggrecanase, ADAMTS5, which is elevated in MPS VI, was reduced by both treatment protocols.</p>", "links"=>[], "tags"=>["articular", "chondrocytes", "untreated", "treated", "mps", "vi"], "article_id"=>414553, "categories"=>["Physiology", "Genetics", "Microbiology", "Immunology"], "users"=>["Efrat Eliyahu", "Theodore Wolfson", "Yi Ge", "Karl J. Jepsen", "Edward H. Schuchman", "Calogera M. Simonaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022447.g005", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Protein_expression_in_articular_chondrocytes_from_untreated_and_treated_MPS_VI_rats_/414553", "title"=>"Protein expression in articular chondrocytes from untreated and treated MPS VI rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 15:34:02"}

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Relative Metric

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