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Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II
Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we re...
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| Published in: | EMBO molecular medicine 2013-12, Vol.5 (12), p.1871-1886 |
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| container_end_page | 1886 |
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| creator | Kollmann, Katrin Pestka, Jan Malte Kühn, Sonja Christin Schöne, Elisabeth Schweizer, Michaela Karkmann, Kathrin Otomo, Takanobu Catala‐Lehnen, Philip Failla, Antonio Virgilio Marshall, Robert Percy Krause, Matthias Santer, Rene Amling, Michael Braulke, Thomas Schinke, Thorsten |
| description | Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock‐in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro‐osteoclastogenic cytokine interleukin‐6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.
Dysfunctional osteoblasts and the Il‐6‐driven osteoclast increase rather than lysosomal hydrolase missorting underlie the osteoporotic phenotype in a mouse model of mucolipidosis II. Bisphosphonate treatment increased bone density and stabilization. |
| doi_str_mv | 10.1002/emmm.201302979 |
| format | article |
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Dysfunctional osteoblasts and the Il‐6‐driven osteoclast increase rather than lysosomal hydrolase missorting underlie the osteoporotic phenotype in a mouse model of mucolipidosis II. Bisphosphonate treatment increased bone density and stabilization.</description><identifier>ISSN: 1757-4676</identifier><identifier>EISSN: 1757-4684</identifier><identifier>DOI: 10.1002/emmm.201302979</identifier><identifier>PMID: 24127423</identifier><language>eng</language><publisher>England: EMBO Press</publisher><subject>alendronate ; Animals ; Bone and Bones - drug effects ; Bone and Bones - metabolism ; Bone and Bones - pathology ; Bone Density Conservation Agents - pharmacology ; Bone Development - genetics ; Bone growth ; Bone loss ; Bone mass ; Bone resorption ; Bones ; Cancellous bone ; Cells, Cultured ; Child, Preschool ; Chondrocytes ; Chondrocytes - cytology ; Chondrocytes - metabolism ; Chondrocytes - pathology ; Cortical bone ; Cytokines ; Defects ; Diphosphonates - pharmacology ; Disease Models, Animal ; Enzymes ; Experiments ; Female ; Genetic disorders ; Genotype & phenotype ; Growth plate ; Humans ; Interleukin-6 - metabolism ; interleukin‐6 ; Macromolecules ; mannose 6‐phosphate ; Mice ; Mice, Inbred C57BL ; Mucolipidoses - diagnostic imaging ; Mucolipidoses - genetics ; Mucolipidoses - pathology ; Mucolipidosis ; mucolipidosis II ; Mutation ; Osteoblasts ; Osteoclastogenesis ; Osteoclasts ; Osteoclasts - cytology ; Osteoclasts - metabolism ; Osteoclasts - pathology ; Osteogenesis ; Osteoporosis ; Phenotypes ; Phenotyping ; Porosity ; Proteins ; Radiography ; RANK Ligand - metabolism ; Storage diseases ; Transferases (Other Substituted Phosphate Groups) - genetics ; Transferases (Other Substituted Phosphate Groups) - metabolism</subject><ispartof>EMBO molecular medicine, 2013-12, Vol.5 (12), p.1871-1886</ispartof><rights>2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO</rights><rights>2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.</rights><rights>2013. This work is published under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5349-2dcb8fe38902c29fc77ba7921ba0e4d5b70bce4fb788ff7851f6bbcf3bc1003c3</citedby><cites>FETCH-LOGICAL-c5349-2dcb8fe38902c29fc77ba7921ba0e4d5b70bce4fb788ff7851f6bbcf3bc1003c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2299121505/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2299121505?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24127423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kollmann, Katrin</creatorcontrib><creatorcontrib>Pestka, Jan Malte</creatorcontrib><creatorcontrib>Kühn, Sonja Christin</creatorcontrib><creatorcontrib>Schöne, Elisabeth</creatorcontrib><creatorcontrib>Schweizer, Michaela</creatorcontrib><creatorcontrib>Karkmann, Kathrin</creatorcontrib><creatorcontrib>Otomo, Takanobu</creatorcontrib><creatorcontrib>Catala‐Lehnen, Philip</creatorcontrib><creatorcontrib>Failla, Antonio Virgilio</creatorcontrib><creatorcontrib>Marshall, Robert Percy</creatorcontrib><creatorcontrib>Krause, Matthias</creatorcontrib><creatorcontrib>Santer, Rene</creatorcontrib><creatorcontrib>Amling, Michael</creatorcontrib><creatorcontrib>Braulke, Thomas</creatorcontrib><creatorcontrib>Schinke, Thorsten</creatorcontrib><title>Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II</title><title>EMBO molecular medicine</title><addtitle>EMBO Mol Med</addtitle><description>Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock‐in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro‐osteoclastogenic cytokine interleukin‐6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.
Dysfunctional osteoblasts and the Il‐6‐driven osteoclast increase rather than lysosomal hydrolase missorting underlie the osteoporotic phenotype in a mouse model of mucolipidosis II. Bisphosphonate treatment increased bone density and stabilization.</description><subject>alendronate</subject><subject>Animals</subject><subject>Bone and Bones - drug effects</subject><subject>Bone and Bones - metabolism</subject><subject>Bone and Bones - pathology</subject><subject>Bone Density Conservation Agents - pharmacology</subject><subject>Bone Development - genetics</subject><subject>Bone growth</subject><subject>Bone loss</subject><subject>Bone mass</subject><subject>Bone resorption</subject><subject>Bones</subject><subject>Cancellous bone</subject><subject>Cells, Cultured</subject><subject>Child, Preschool</subject><subject>Chondrocytes</subject><subject>Chondrocytes - cytology</subject><subject>Chondrocytes - metabolism</subject><subject>Chondrocytes - pathology</subject><subject>Cortical bone</subject><subject>Cytokines</subject><subject>Defects</subject><subject>Diphosphonates - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Enzymes</subject><subject>Experiments</subject><subject>Female</subject><subject>Genetic disorders</subject><subject>Genotype & phenotype</subject><subject>Growth plate</subject><subject>Humans</subject><subject>Interleukin-6 - metabolism</subject><subject>interleukin‐6</subject><subject>Macromolecules</subject><subject>mannose 6‐phosphate</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mucolipidoses - diagnostic imaging</subject><subject>Mucolipidoses - genetics</subject><subject>Mucolipidoses - pathology</subject><subject>Mucolipidosis</subject><subject>mucolipidosis II</subject><subject>Mutation</subject><subject>Osteoblasts</subject><subject>Osteoclastogenesis</subject><subject>Osteoclasts</subject><subject>Osteoclasts - cytology</subject><subject>Osteoclasts - metabolism</subject><subject>Osteoclasts - pathology</subject><subject>Osteogenesis</subject><subject>Osteoporosis</subject><subject>Phenotypes</subject><subject>Phenotyping</subject><subject>Porosity</subject><subject>Proteins</subject><subject>Radiography</subject><subject>RANK Ligand - metabolism</subject><subject>Storage diseases</subject><subject>Transferases (Other Substituted Phosphate Groups) - genetics</subject><subject>Transferases (Other Substituted Phosphate Groups) - 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drug effects</topic><topic>Bone and Bones - metabolism</topic><topic>Bone and Bones - pathology</topic><topic>Bone Density Conservation Agents - pharmacology</topic><topic>Bone Development - genetics</topic><topic>Bone growth</topic><topic>Bone loss</topic><topic>Bone mass</topic><topic>Bone resorption</topic><topic>Bones</topic><topic>Cancellous bone</topic><topic>Cells, Cultured</topic><topic>Child, Preschool</topic><topic>Chondrocytes</topic><topic>Chondrocytes - cytology</topic><topic>Chondrocytes - metabolism</topic><topic>Chondrocytes - pathology</topic><topic>Cortical bone</topic><topic>Cytokines</topic><topic>Defects</topic><topic>Diphosphonates - pharmacology</topic><topic>Disease Models, Animal</topic><topic>Enzymes</topic><topic>Experiments</topic><topic>Female</topic><topic>Genetic disorders</topic><topic>Genotype & phenotype</topic><topic>Growth plate</topic><topic>Humans</topic><topic>Interleukin-6 - metabolism</topic><topic>interleukin‐6</topic><topic>Macromolecules</topic><topic>mannose 6‐phosphate</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mucolipidoses - 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Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EMBO molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kollmann, Katrin</au><au>Pestka, Jan Malte</au><au>Kühn, Sonja Christin</au><au>Schöne, Elisabeth</au><au>Schweizer, Michaela</au><au>Karkmann, Kathrin</au><au>Otomo, Takanobu</au><au>Catala‐Lehnen, Philip</au><au>Failla, Antonio Virgilio</au><au>Marshall, Robert Percy</au><au>Krause, Matthias</au><au>Santer, Rene</au><au>Amling, Michael</au><au>Braulke, Thomas</au><au>Schinke, Thorsten</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II</atitle><jtitle>EMBO molecular medicine</jtitle><addtitle>EMBO Mol Med</addtitle><date>2013-12</date><risdate>2013</risdate><volume>5</volume><issue>12</issue><spage>1871</spage><epage>1886</epage><pages>1871-1886</pages><issn>1757-4676</issn><eissn>1757-4684</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>These authors contributed equally to this work</notes><abstract>Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock‐in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro‐osteoclastogenic cytokine interleukin‐6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.
Dysfunctional osteoblasts and the Il‐6‐driven osteoclast increase rather than lysosomal hydrolase missorting underlie the osteoporotic phenotype in a mouse model of mucolipidosis II. Bisphosphonate treatment increased bone density and stabilization.</abstract><cop>England</cop><pub>EMBO Press</pub><pmid>24127423</pmid><doi>10.1002/emmm.201302979</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1757-4676 |
| ispartof | EMBO molecular medicine, 2013-12, Vol.5 (12), p.1871-1886 |
| issn | 1757-4676 1757-4684 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3914524 |
| source | ProQuest - Publicly Available Content Database; PubMed Central |
| subjects | alendronate Animals Bone and Bones - drug effects Bone and Bones - metabolism Bone and Bones - pathology Bone Density Conservation Agents - pharmacology Bone Development - genetics Bone growth Bone loss Bone mass Bone resorption Bones Cancellous bone Cells, Cultured Child, Preschool Chondrocytes Chondrocytes - cytology Chondrocytes - metabolism Chondrocytes - pathology Cortical bone Cytokines Defects Diphosphonates - pharmacology Disease Models, Animal Enzymes Experiments Female Genetic disorders Genotype & phenotype Growth plate Humans Interleukin-6 - metabolism interleukin‐6 Macromolecules mannose 6‐phosphate Mice Mice, Inbred C57BL Mucolipidoses - diagnostic imaging Mucolipidoses - genetics Mucolipidoses - pathology Mucolipidosis mucolipidosis II Mutation Osteoblasts Osteoclastogenesis Osteoclasts Osteoclasts - cytology Osteoclasts - metabolism Osteoclasts - pathology Osteogenesis Osteoporosis Phenotypes Phenotyping Porosity Proteins Radiography RANK Ligand - metabolism Storage diseases Transferases (Other Substituted Phosphate Groups) - genetics Transferases (Other Substituted Phosphate Groups) - metabolism |
| title | Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T11%3A38%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Decreased%20bone%20formation%20and%20increased%20osteoclastogenesis%20cause%20bone%20loss%20in%20mucolipidosis%20II&rft.jtitle=EMBO%20molecular%20medicine&rft.au=Kollmann,%20Katrin&rft.date=2013-12&rft.volume=5&rft.issue=12&rft.spage=1871&rft.epage=1886&rft.pages=1871-1886&rft.issn=1757-4676&rft.eissn=1757-4684&rft_id=info:doi/10.1002/emmm.201302979&rft_dat=%3Cproquest_pubme%3E2299121505%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c5349-2dcb8fe38902c29fc77ba7921ba0e4d5b70bce4fb788ff7851f6bbcf3bc1003c3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2299121505&rft_id=info:pmid/24127423&rfr_iscdi=true |