Multiple roles for neurofibromin in skeletal development and growth
Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder primarily characterized by the formation of neurofibromas, café-au-lait spots and freckling. Skeletal abnormalities such as short stature or bowing/pseudarthrosis of the tibia are relatively common. To investigate the role of the neurofi...
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| Veröffentlicht in: | Human molecular genetics 2007-04, Vol.16 (8), p.874-886 |
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| creator | Kolanczyk, Mateusz Kossler, Nadine Kühnisch, Jirko Lavitas, Liron Stricker, Sigmar Wilkening, Ulrich Manjubala, Inderchand Fratzl, Peter Spörle, Ralf Herrmann, Bernhard G. Parada, Luis F. Kornak, Uwe Mundlos, Stefan |
| description | Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder primarily characterized by the formation of neurofibromas, café-au-lait spots and freckling. Skeletal abnormalities such as short stature or bowing/pseudarthrosis of the tibia are relatively common. To investigate the role of the neurofibromin in skeletal development, we crossed Nf1flox mice with Prx1Cre mice to inactivate Nf1 in undifferentiated mesenchymal cells of the developing limbs. Similar to NF1 affected individuals, Nf1Prx1 mice show bowing of the tibia and diminished growth. Tibial bowing is caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness and reduction in the mineral content as well as hyperosteoidosis. Accordingly, osteoblasts show an increase in proliferation and a decreased ability to differentiate and mineralize in vitro. The reduction in growth is due to lower proliferation rates and a differentiation defect of chondrocytes. Abnormal vascularization of skeletal tissues is likely to contribute to this pathology as it exerts a negative effect on cortical bone stability. Furthermore, Nf1 has an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities, which are not observed in neurofibromatosis type I. Thus, neurofibromin has multiple essential roles in skeletal development and growth. |
| doi_str_mv | 10.1093/hmg/ddm032 |
| format | Article |
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Skeletal abnormalities such as short stature or bowing/pseudarthrosis of the tibia are relatively common. To investigate the role of the neurofibromin in skeletal development, we crossed Nf1flox mice with Prx1Cre mice to inactivate Nf1 in undifferentiated mesenchymal cells of the developing limbs. Similar to NF1 affected individuals, Nf1Prx1 mice show bowing of the tibia and diminished growth. Tibial bowing is caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness and reduction in the mineral content as well as hyperosteoidosis. Accordingly, osteoblasts show an increase in proliferation and a decreased ability to differentiate and mineralize in vitro. The reduction in growth is due to lower proliferation rates and a differentiation defect of chondrocytes. Abnormal vascularization of skeletal tissues is likely to contribute to this pathology as it exerts a negative effect on cortical bone stability. Furthermore, Nf1 has an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities, which are not observed in neurofibromatosis type I. Thus, neurofibromin has multiple essential roles in skeletal development and growth.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddm032</identifier><identifier>PMID: 17317783</identifier><identifier>CODEN: HNGEE5</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Animals ; Animals, Newborn ; Biological and medical sciences ; Bone and Bones - blood supply ; Bone and Bones - embryology ; Bone and Bones - physiology ; Bone Development - genetics ; Bone Diseases, Developmental - genetics ; Cell Differentiation - genetics ; Cell Proliferation ; Cells, Cultured ; Fundamental and applied biological sciences. Psychology ; Genetics of eukaryotes. Biological and molecular evolution ; Joints - embryology ; Joints - growth & development ; Mice ; Mice, Transgenic ; Molecular and cellular biology ; Neovascularization, Pathologic - genetics ; Neurofibromin 1 - genetics ; Neurofibromin 1 - physiology ; Osteoblasts - cytology</subject><ispartof>Human molecular genetics, 2007-04, Vol.16 (8), p.874-886</ispartof><rights>2007 The Author(s) 2007</rights><rights>2007 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Apr 15, 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-f1dd8ba70b5a7b433030e95d072ba705bf612bcbc6d17720ee208cba7c97c4593</citedby><cites>FETCH-LOGICAL-c477t-f1dd8ba70b5a7b433030e95d072ba705bf612bcbc6d17720ee208cba7c97c4593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1578,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18755927$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17317783$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kolanczyk, Mateusz</creatorcontrib><creatorcontrib>Kossler, Nadine</creatorcontrib><creatorcontrib>Kühnisch, Jirko</creatorcontrib><creatorcontrib>Lavitas, Liron</creatorcontrib><creatorcontrib>Stricker, Sigmar</creatorcontrib><creatorcontrib>Wilkening, Ulrich</creatorcontrib><creatorcontrib>Manjubala, Inderchand</creatorcontrib><creatorcontrib>Fratzl, Peter</creatorcontrib><creatorcontrib>Spörle, Ralf</creatorcontrib><creatorcontrib>Herrmann, Bernhard G.</creatorcontrib><creatorcontrib>Parada, Luis F.</creatorcontrib><creatorcontrib>Kornak, Uwe</creatorcontrib><creatorcontrib>Mundlos, Stefan</creatorcontrib><title>Multiple roles for neurofibromin in skeletal development and growth</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder primarily characterized by the formation of neurofibromas, café-au-lait spots and freckling. Skeletal abnormalities such as short stature or bowing/pseudarthrosis of the tibia are relatively common. To investigate the role of the neurofibromin in skeletal development, we crossed Nf1flox mice with Prx1Cre mice to inactivate Nf1 in undifferentiated mesenchymal cells of the developing limbs. Similar to NF1 affected individuals, Nf1Prx1 mice show bowing of the tibia and diminished growth. Tibial bowing is caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness and reduction in the mineral content as well as hyperosteoidosis. Accordingly, osteoblasts show an increase in proliferation and a decreased ability to differentiate and mineralize in vitro. The reduction in growth is due to lower proliferation rates and a differentiation defect of chondrocytes. Abnormal vascularization of skeletal tissues is likely to contribute to this pathology as it exerts a negative effect on cortical bone stability. Furthermore, Nf1 has an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities, which are not observed in neurofibromatosis type I. Thus, neurofibromin has multiple essential roles in skeletal development and growth.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Biological and medical sciences</subject><subject>Bone and Bones - blood supply</subject><subject>Bone and Bones - embryology</subject><subject>Bone and Bones - physiology</subject><subject>Bone Development - genetics</subject><subject>Bone Diseases, Developmental - genetics</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Joints - embryology</subject><subject>Joints - growth & development</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Molecular and cellular biology</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>Neurofibromin 1 - genetics</subject><subject>Neurofibromin 1 - physiology</subject><subject>Osteoblasts - cytology</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0UGLEzEUB_Agiu1WL34AGQQ9CGNfJjNJc9wWdytU9KAiXkImedOd3cxkTGZc_famtFjwoPAgkPx4ycufkGcU3lCQbHnT7ZfWdsCKB2ROSw55ASv2kMxB8jLnEviMXMR4C0B5ycRjMqOCUSFWbE427yc3toPDLHiHMWt8yHqcgm_aOviu7bNU8Q4djtplFn-g80OH_Zjp3mb74O_HmyfkUaNdxKendUE-X739tNnmuw_X7zaXu9yUQox5Q61d1VpAXWlRl4wBA5SVBVEcdqu64bSoTW24TY8rADGNYdKRkcKUlWQL8urYdwj--4RxVF0bDTqne_RTVALKKhX_L6SSi5LyIsEXf8FbP4U-DaEKShmVDGhCr4_IBB9jwEYNoe10-KUoqEMAKgWgjgEk_PzUcao7tGd6-vEEXp6Ajka7JujetPHsVqKqZCHOzk_Dvy_Mj66NI_78I3W4U1wwUant12_qy06u1x_pTq3Zb1Ywqb4</recordid><startdate>20070415</startdate><enddate>20070415</enddate><creator>Kolanczyk, Mateusz</creator><creator>Kossler, Nadine</creator><creator>Kühnisch, Jirko</creator><creator>Lavitas, Liron</creator><creator>Stricker, Sigmar</creator><creator>Wilkening, Ulrich</creator><creator>Manjubala, Inderchand</creator><creator>Fratzl, Peter</creator><creator>Spörle, Ralf</creator><creator>Herrmann, Bernhard G.</creator><creator>Parada, Luis F.</creator><creator>Kornak, Uwe</creator><creator>Mundlos, Stefan</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20070415</creationdate><title>Multiple roles for neurofibromin in skeletal development and growth</title><author>Kolanczyk, Mateusz ; Kossler, Nadine ; Kühnisch, Jirko ; Lavitas, Liron ; Stricker, Sigmar ; Wilkening, Ulrich ; Manjubala, Inderchand ; Fratzl, Peter ; Spörle, Ralf ; Herrmann, Bernhard G. ; Parada, Luis F. ; Kornak, Uwe ; Mundlos, Stefan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-f1dd8ba70b5a7b433030e95d072ba705bf612bcbc6d17720ee208cba7c97c4593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Biological and medical sciences</topic><topic>Bone and Bones - blood supply</topic><topic>Bone and Bones - embryology</topic><topic>Bone and Bones - physiology</topic><topic>Bone Development - genetics</topic><topic>Bone Diseases, Developmental - genetics</topic><topic>Cell Differentiation - genetics</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Fundamental and applied biological sciences. 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Skeletal abnormalities such as short stature or bowing/pseudarthrosis of the tibia are relatively common. To investigate the role of the neurofibromin in skeletal development, we crossed Nf1flox mice with Prx1Cre mice to inactivate Nf1 in undifferentiated mesenchymal cells of the developing limbs. Similar to NF1 affected individuals, Nf1Prx1 mice show bowing of the tibia and diminished growth. Tibial bowing is caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness and reduction in the mineral content as well as hyperosteoidosis. Accordingly, osteoblasts show an increase in proliferation and a decreased ability to differentiate and mineralize in vitro. The reduction in growth is due to lower proliferation rates and a differentiation defect of chondrocytes. Abnormal vascularization of skeletal tissues is likely to contribute to this pathology as it exerts a negative effect on cortical bone stability. Furthermore, Nf1 has an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities, which are not observed in neurofibromatosis type I. Thus, neurofibromin has multiple essential roles in skeletal development and growth.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>17317783</pmid><doi>10.1093/hmg/ddm032</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Animals, Newborn Biological and medical sciences Bone and Bones - blood supply Bone and Bones - embryology Bone and Bones - physiology Bone Development - genetics Bone Diseases, Developmental - genetics Cell Differentiation - genetics Cell Proliferation Cells, Cultured Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Joints - embryology Joints - growth & development Mice Mice, Transgenic Molecular and cellular biology Neovascularization, Pathologic - genetics Neurofibromin 1 - genetics Neurofibromin 1 - physiology Osteoblasts - cytology |
| title | Multiple roles for neurofibromin in skeletal development and growth |
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