Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals
Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways...
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| Veröffentlicht in: | Cell 2008-03, Vol.132 (5), p.794-806 |
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| creator | Shinohara, Masahiro Koga, Takako Okamoto, Kazuo Sakaguchi, Shinya Arai, Kimiko Yasuda, Hisataka Takai, Toshiyuki Kodama, Tatsuhiko Morio, Tomohiro Geha, Raif S. Kitamura, Daisuke Kurosaki, Tomohiro Ellmeier, Wilfried Takayanagi, Hiroshi |
| description | Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways activated by RANK and immune receptors linked to ITAM-harboring adaptors. However, it is unclear how the two signals merge to cooperate in osteoclast differentiation. Here we report that mice lacking the tyrosine kinases Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. RANK and ITAM signaling results in formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLCγ-mediated activation of an essential calcium signal. Furthermore, Tec kinase inhibition reduces osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy. |
| doi_str_mv | 10.1016/j.cell.2007.12.037 |
| format | Article |
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Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways activated by RANK and immune receptors linked to ITAM-harboring adaptors. However, it is unclear how the two signals merge to cooperate in osteoclast differentiation. Here we report that mice lacking the tyrosine kinases Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. RANK and ITAM signaling results in formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLCγ-mediated activation of an essential calcium signal. Furthermore, Tec kinase inhibition reduces osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2007.12.037</identifier><identifier>PMID: 18329366</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Amino Acid Motifs ; Animals ; Bone and Bones - cytology ; Bone and Bones - metabolism ; Calcium Signaling ; Cell Differentiation ; Disease Models, Animal ; Female ; HUMDISEASE ; Mice ; MOLIMMUNO ; Osteoclasts - cytology ; Osteoclasts - metabolism ; Osteopetrosis - drug therapy ; Osteopetrosis - genetics ; Osteopetrosis - metabolism ; Osteoporosis - metabolism ; Osteoporosis - pathology ; Phospholipase C gamma - metabolism ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - genetics ; Protein-Tyrosine Kinases - metabolism ; RANK Ligand - metabolism ; RANK Ligand - pharmacology ; Signal Transduction ; SIGNALING</subject><ispartof>Cell, 2008-03, Vol.132 (5), p.794-806</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c495t-aef71e9c38438068dca9d13a295da223a8a23fe5f90f8f37fb8738917cac76b53</citedby><cites>FETCH-LOGICAL-c495t-aef71e9c38438068dca9d13a295da223a8a23fe5f90f8f37fb8738917cac76b53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867408000585$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18329366$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shinohara, Masahiro</creatorcontrib><creatorcontrib>Koga, Takako</creatorcontrib><creatorcontrib>Okamoto, Kazuo</creatorcontrib><creatorcontrib>Sakaguchi, Shinya</creatorcontrib><creatorcontrib>Arai, Kimiko</creatorcontrib><creatorcontrib>Yasuda, Hisataka</creatorcontrib><creatorcontrib>Takai, Toshiyuki</creatorcontrib><creatorcontrib>Kodama, Tatsuhiko</creatorcontrib><creatorcontrib>Morio, Tomohiro</creatorcontrib><creatorcontrib>Geha, Raif S.</creatorcontrib><creatorcontrib>Kitamura, Daisuke</creatorcontrib><creatorcontrib>Kurosaki, Tomohiro</creatorcontrib><creatorcontrib>Ellmeier, Wilfried</creatorcontrib><creatorcontrib>Takayanagi, Hiroshi</creatorcontrib><title>Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals</title><title>Cell</title><addtitle>Cell</addtitle><description>Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. 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Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Amino Acid Motifs</subject><subject>Animals</subject><subject>Bone and Bones - cytology</subject><subject>Bone and Bones - metabolism</subject><subject>Calcium Signaling</subject><subject>Cell Differentiation</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>HUMDISEASE</subject><subject>Mice</subject><subject>MOLIMMUNO</subject><subject>Osteoclasts - cytology</subject><subject>Osteoclasts - metabolism</subject><subject>Osteopetrosis - drug therapy</subject><subject>Osteopetrosis - genetics</subject><subject>Osteopetrosis - metabolism</subject><subject>Osteoporosis - metabolism</subject><subject>Osteoporosis - pathology</subject><subject>Phospholipase C gamma - metabolism</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - genetics</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>RANK Ligand - metabolism</subject><subject>RANK Ligand - pharmacology</subject><subject>Signal Transduction</subject><subject>SIGNALING</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkTtPIzEYRa0VaMkCf2CLlSu6GfwYj22JJjx2QQSQINSW4_kcOUw8MHaQ8u93QiLRQXWbc09xL0K_KSkpofXponTQtiUjRJaUlYTLH2hEiZZFRSXbQyNCNCtULasD9CulBSFECSF-ogOqONO8rkfITtd9l0IEfBuiTZDweX7BNjZ4Cg4_wnzV2gz4IWXoXGtTxpfBe-gh5mBz6CKerfEkxJcQ5_hxfH_70b2Zju_wU5hH26YjtO-HgONdHqLnv1fTi-ti8vDv5mI8KVylRS4seElBO64qrkitGmd1Q7llWjSWMW6VZdyD8Jp45bn0MyW50lQ662Q9E_wQnWy9r333toKUzTKkzUA2QrdKRpLBK0T9LciIqKqK0QFkW9ANE6UevHntw9L2a0OJ2TxgFmbTM5sHDGVmeGAo_dnZV7MlNJ-V3eQDcLYFYBjjPUBvkgsQHTShB5dN04Wv_P8ByV6Wmg</recordid><startdate>20080307</startdate><enddate>20080307</enddate><creator>Shinohara, Masahiro</creator><creator>Koga, Takako</creator><creator>Okamoto, Kazuo</creator><creator>Sakaguchi, Shinya</creator><creator>Arai, Kimiko</creator><creator>Yasuda, Hisataka</creator><creator>Takai, Toshiyuki</creator><creator>Kodama, Tatsuhiko</creator><creator>Morio, Tomohiro</creator><creator>Geha, Raif S.</creator><creator>Kitamura, Daisuke</creator><creator>Kurosaki, Tomohiro</creator><creator>Ellmeier, Wilfried</creator><creator>Takayanagi, Hiroshi</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20080307</creationdate><title>Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals</title><author>Shinohara, Masahiro ; Koga, Takako ; Okamoto, Kazuo ; Sakaguchi, Shinya ; Arai, Kimiko ; Yasuda, Hisataka ; Takai, Toshiyuki ; Kodama, Tatsuhiko ; Morio, Tomohiro ; Geha, Raif S. ; Kitamura, Daisuke ; Kurosaki, Tomohiro ; Ellmeier, Wilfried ; Takayanagi, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c495t-aef71e9c38438068dca9d13a295da223a8a23fe5f90f8f37fb8738917cac76b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Amino Acid Motifs</topic><topic>Animals</topic><topic>Bone and Bones - cytology</topic><topic>Bone and Bones - metabolism</topic><topic>Calcium Signaling</topic><topic>Cell Differentiation</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>HUMDISEASE</topic><topic>Mice</topic><topic>MOLIMMUNO</topic><topic>Osteoclasts - cytology</topic><topic>Osteoclasts - metabolism</topic><topic>Osteopetrosis - drug therapy</topic><topic>Osteopetrosis - genetics</topic><topic>Osteopetrosis - metabolism</topic><topic>Osteoporosis - metabolism</topic><topic>Osteoporosis - pathology</topic><topic>Phospholipase C gamma - metabolism</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Protein-Tyrosine Kinases - genetics</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>RANK Ligand - metabolism</topic><topic>RANK Ligand - pharmacology</topic><topic>Signal Transduction</topic><topic>SIGNALING</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shinohara, Masahiro</creatorcontrib><creatorcontrib>Koga, Takako</creatorcontrib><creatorcontrib>Okamoto, Kazuo</creatorcontrib><creatorcontrib>Sakaguchi, Shinya</creatorcontrib><creatorcontrib>Arai, Kimiko</creatorcontrib><creatorcontrib>Yasuda, Hisataka</creatorcontrib><creatorcontrib>Takai, Toshiyuki</creatorcontrib><creatorcontrib>Kodama, Tatsuhiko</creatorcontrib><creatorcontrib>Morio, Tomohiro</creatorcontrib><creatorcontrib>Geha, Raif S.</creatorcontrib><creatorcontrib>Kitamura, Daisuke</creatorcontrib><creatorcontrib>Kurosaki, Tomohiro</creatorcontrib><creatorcontrib>Ellmeier, Wilfried</creatorcontrib><creatorcontrib>Takayanagi, Hiroshi</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shinohara, Masahiro</au><au>Koga, Takako</au><au>Okamoto, Kazuo</au><au>Sakaguchi, Shinya</au><au>Arai, Kimiko</au><au>Yasuda, Hisataka</au><au>Takai, Toshiyuki</au><au>Kodama, Tatsuhiko</au><au>Morio, Tomohiro</au><au>Geha, Raif S.</au><au>Kitamura, Daisuke</au><au>Kurosaki, Tomohiro</au><au>Ellmeier, Wilfried</au><au>Takayanagi, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2008-03-07</date><risdate>2008</risdate><volume>132</volume><issue>5</issue><spage>794</spage><epage>806</epage><pages>794-806</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways activated by RANK and immune receptors linked to ITAM-harboring adaptors. However, it is unclear how the two signals merge to cooperate in osteoclast differentiation. Here we report that mice lacking the tyrosine kinases Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. RANK and ITAM signaling results in formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLCγ-mediated activation of an essential calcium signal. Furthermore, Tec kinase inhibition reduces osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18329366</pmid><doi>10.1016/j.cell.2007.12.037</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Amino Acid Motifs Animals Bone and Bones - cytology Bone and Bones - metabolism Calcium Signaling Cell Differentiation Disease Models, Animal Female HUMDISEASE Mice MOLIMMUNO Osteoclasts - cytology Osteoclasts - metabolism Osteopetrosis - drug therapy Osteopetrosis - genetics Osteopetrosis - metabolism Osteoporosis - metabolism Osteoporosis - pathology Phospholipase C gamma - metabolism Phosphoproteins - genetics Phosphoproteins - metabolism Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism RANK Ligand - metabolism RANK Ligand - pharmacology Signal Transduction SIGNALING |
| title | Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals |
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