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dc.contributor.authorOdgren, Paul R.
dc.contributor.authorKim, Nacksung
dc.contributor.authorvan Wesenbeeck, Liesbeth
dc.contributor.authorMacKay, Carole A.
dc.contributor.authorMason-Savas, April
dc.contributor.authorSafadi, Fayez F.
dc.contributor.authorPopoff, Steven N.
dc.contributor.authorLengner, Christopher J.
dc.contributor.authorvan-Hul, Wim
dc.contributor.authorChoi, Yongwon
dc.contributor.authorMarks, Sandy C. Jr.
dc.date2022-08-11T08:10:03.000
dc.date.accessioned2022-08-23T16:53:25Z
dc.date.available2022-08-23T16:53:25Z
dc.date.issued2002-01-24
dc.date.submitted2008-07-15
dc.identifier.citationInt J Dev Biol. 2001 Dec;45(8):853-9.
dc.identifier.issn0214-6282 (Print)
dc.identifier.pmid11804028
dc.identifier.urihttp://hdl.handle.net/20.500.14038/42270
dc.description.abstractThe toothless (tl) osteopetrotic mutation in the rat affects an osteoblast-derived factor that is required for normal osteoclast differentiation. Although the genetic locus remains unknown, the phenotypic impact of the tl mutation on multiple systems has been well characterized. Some of its actions are similar to tumornecrosis factor superfamily member 11(TNFSF11; also called TRANCE, RANKL, ODF and OPGL) null mice. TNFSF11 is a recently described member of the tumor necrosis factor superfamily which, when expressed by activated T cells, enhances the survival of antigen-presenting dendritic cells, and when expressed by osteoblasts, promotes the differentiation and activation of osteoclasts. The skeletal similarities between tl rats and TNFSF11(-/-) mice include 1) profound osteoclastopenia (TNFSF11-null mice, 0% and tl rats 0-1% of normal); 2) persistent, non-resolving osteopetrosis that results from 3) a defect not in the osteoclast lineage itself, but in an osteoblast-derived, osteoclastogenic signal; and 4) a severe chondrodysplasia of the growth plates of long bones not seen in other osteopetrotic mutations. The latter includes thickening of the growth plate with age, disorganization of chondrocyte columns, and disturbances of chondrocyte maturation. These striking similarities prompted us to undertake studies to rule in or out a TNFSF11 mutation in the tl rat. We looked for expression of TNFSF11 mRNA in tl long bones and found it to be over-expressed and of the correct size. We also tested TNFSF11 protein function in the tl rat. This was shown to be normal by flow cytometry experiments in which activated, spleen-derived T-cells from tl rats exhibited normal receptor binding competence, as measured by a recombinant receptor assay. We also found that tl rats develop histologically normal mesenteric and peripheral lymph nodes, which are absent from TNFSF11-null mice. Next, we found that injections of recombinant TNFSF11, which restores bone resorption in null mice, had no therapeutic effect in tl rats. Finally, gene mapping studies using co-segregation of polymorphic markers excluded the chromosomal region containing the TNFSF11 gene as harboring the mutation responsible for the tl phenotype. We conclude that, despite substantial phenotypic similarities to TNFSF11(-/-) mice, the tl rat mutation is not in the TNFSF11 locus, and that its identification must await the results of further studies.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=11804028&dopt=Abstract">Link to Article in PubMed</a>
dc.subjectAnimals
dc.subjectBone Resorption
dc.subjectCarrier Proteins
dc.subjectChromosome Mapping
dc.subjectChromosomes
dc.subjectFlow Cytometry
dc.subjectHumans
dc.subjectLymph Nodes
dc.subjectMembrane Glycoproteins
dc.subjectMice
dc.subjectMice, Knockout
dc.subjectOsteoclasts
dc.subjectOsteopetrosis
dc.subjectPhenotype
dc.subjectRANK Ligand
dc.subjectRats
dc.subjectReceptor Activator of Nuclear Factor-kappa B
dc.subjectTumor Necrosis Factor-alpha
dc.subjectAnatomy
dc.subjectCell Biology
dc.titleEvidence that the rat osteopetrotic mutation toothless (tl) is not in the TNFSF11 (TRANCE, RANKL, ODF, OPGL) gene
dc.typeJournal Article
dc.source.journaltitleThe International journal of developmental biology
dc.source.volume45
dc.source.issue8
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1631&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/632
dc.identifier.contextkey549061
refterms.dateFOA2022-08-23T16:53:25Z
html.description.abstract<p>The toothless (tl) osteopetrotic mutation in the rat affects an osteoblast-derived factor that is required for normal osteoclast differentiation. Although the genetic locus remains unknown, the phenotypic impact of the tl mutation on multiple systems has been well characterized. Some of its actions are similar to tumornecrosis factor superfamily member 11(TNFSF11; also called TRANCE, RANKL, ODF and OPGL) null mice. TNFSF11 is a recently described member of the tumor necrosis factor superfamily which, when expressed by activated T cells, enhances the survival of antigen-presenting dendritic cells, and when expressed by osteoblasts, promotes the differentiation and activation of osteoclasts. The skeletal similarities between tl rats and TNFSF11(-/-) mice include 1) profound osteoclastopenia (TNFSF11-null mice, 0% and tl rats 0-1% of normal); 2) persistent, non-resolving osteopetrosis that results from 3) a defect not in the osteoclast lineage itself, but in an osteoblast-derived, osteoclastogenic signal; and 4) a severe chondrodysplasia of the growth plates of long bones not seen in other osteopetrotic mutations. The latter includes thickening of the growth plate with age, disorganization of chondrocyte columns, and disturbances of chondrocyte maturation. These striking similarities prompted us to undertake studies to rule in or out a TNFSF11 mutation in the tl rat. We looked for expression of TNFSF11 mRNA in tl long bones and found it to be over-expressed and of the correct size. We also tested TNFSF11 protein function in the tl rat. This was shown to be normal by flow cytometry experiments in which activated, spleen-derived T-cells from tl rats exhibited normal receptor binding competence, as measured by a recombinant receptor assay. We also found that tl rats develop histologically normal mesenteric and peripheral lymph nodes, which are absent from TNFSF11-null mice. Next, we found that injections of recombinant TNFSF11, which restores bone resorption in null mice, had no therapeutic effect in tl rats. Finally, gene mapping studies using co-segregation of polymorphic markers excluded the chromosomal region containing the TNFSF11 gene as harboring the mutation responsible for the tl phenotype. We conclude that, despite substantial phenotypic similarities to TNFSF11(-/-) mice, the tl rat mutation is not in the TNFSF11 locus, and that its identification must await the results of further studies.</p>
dc.identifier.submissionpathoapubs/632
dc.contributor.departmentDepartment of Anatomy
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages853-9


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