{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:02:25Z","timestamp":1791838945691,"version":"4.3.4"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,1,5]]},"abstract":"<jats:p>\n                    Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-\u03b1 drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4\n                    <jats:sup>(lps\u2212\/\u2212)<\/jats:sup>\n                    ) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-\u03b1 were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-\u03b1, receptor activator of NF-\u03baB, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-month-old animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-\u03b1 may have positive therapeutic effects.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0912937107","type":"journal-article","created":{"date-parts":[[2009,12,14]],"date-time":"2009-12-14T22:19:27Z","timestamp":1260829167000},"page":"222-227","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":162,"title":["Involvement of the Toll-like receptor 4 pathway and use of TNF-\u03b1 antagonists for treatment of the mucopolysaccharidoses"],"prefix":"10.1073","volume":"107","author":[{"given":"Calogera M.","family":"Simonaro","sequence":"first","affiliation":[{"name":"Departments of aGenetics and Genomic Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Ge","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and Genomic Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efrat","family":"Eliyahu","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and Genomic Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxuan","family":"He","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and Genomic Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl J.","family":"Jepsen","sequence":"additional","affiliation":[{"name":"Orthopaedics, Mount Sinai School of Medicine, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward H.","family":"Schuchman","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and Genomic Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,12,29]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"3421","volume-title":"Metabolic and Molecular Basis of Inherited Disease","author":"Neufeld EF","year":"2001","unstructured":"EF Neufeld, J Meunzer, The mucopolysaccharidoses. Metabolic and Molecular Basis of Inherited Disease, eds CR Scriver, Al Beaudet, WS Sly, D Valle (McGraw\u2013Hill, New York), pp. 3421\u20133452 (2001)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399408000550"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3780345"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000156510.96253.5A"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070564"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002296"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2009.03.005"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8417-2-4"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4906(02)02233-0"},{"key":"e_1_3_3_10_2","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.4049\/jimmunol.162.7.3749","article-title":"Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the Lps gene product","volume":"162","author":"Hoshino K","year":"1999","unstructured":"K Hoshino, et al., Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the Lps gene product. J Immunol 162, 3749\u20133752 (1999).","journal-title":"J Immunol"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M606352200"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.03.112"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199906000-00010"},{"key":"e_1_3_3_14_2","first-page":"100","article-title":"Enzyme replacement therapy for lysosomal storage disorders: Successful transition from concept to clinical practice","volume":"101","author":"Sly WS","year":"2004","unstructured":"WS Sly, Enzyme replacement therapy for lysosomal storage disorders: Successful transition from concept to clinical practice. Mo Med 101, 100\u2013104 (2004).","journal-title":"Mo Med"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200767180-00005"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.5227"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(08)04021-4"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601623"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.3.7545"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.3678"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(95)80217-7"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.037929"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1206763"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0804144"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21779"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.3109\/s10165-004-0275-8"},{"key":"e_1_3_3_27_2","first-page":"S237","article-title":"Improved health-related quality of life with effective disease-modifying antirheumatic drugs: Evidence from randomized controlled trials","volume":"13","author":"Strand V","year":"2007","unstructured":"V Strand, JA Singh, Improved health-related quality of life with effective disease-modifying antirheumatic drugs: Evidence from randomized controlled trials. Am J Manag Care 13, S237\u2013S251 (2007).","journal-title":"Am J Manag Care"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24275"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2009.03997.x"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.20.9784"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.23608"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.3109\/s10165-008-0142-0"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24367"},{"key":"e_1_3_3_34_2","first-page":"204","article-title":"Osteoclastogenesis\u2014Current knowledge and future perspectives","volume":"8","author":"Yavropoulou MP","year":"2008","unstructured":"MP Yavropoulou, JG Yovos, Osteoclastogenesis\u2014Current knowledge and future perspectives. J Musculoskelet Neuronal Interact 8, 204\u2013216 (2008).","journal-title":"J Musculoskelet Neuronal Interact"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.14.6567"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.4.2106"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5396.2085"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116268"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1995.9962"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2001.5108"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2009.02.048"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0912937107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T18:08:31Z","timestamp":1685210911000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0912937107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12,29]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2010,1,5]]}},"alternative-id":["10.1073\/pnas.0912937107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0912937107","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,12,29]]},"assertion":[{"value":"2009-12-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}