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c‐Jun N‐Terminal Kinases (JNKs) Are Critical Mediators of Osteoblast Activity In Vivo
ABSTRACT The c‐Jun N‐terminal kinases (JNKs) are ancient and evolutionarily conserved regulators of proliferation, differentiation, and cell death responses. Currently, in vitro studies offer conflicting data about whether the JNK pathway augments or represses osteoblast differentiation, and the con...
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Published in: | Journal of bone and mineral research 2017-09, Vol.32 (9), p.1811-1815 |
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container_title | Journal of bone and mineral research |
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creator | Xu, Ren Zhang, Chao Shin, Dong Yeon Kim, Jung‐Min Lalani, Sarfaraz Li, Na Yang, Yeon‐Suk Liu, Yifang Eiseman, Mark Davis, Roger J Shim, Jae‐Hyuck Greenblatt, Matthew B |
description | ABSTRACT
The c‐Jun N‐terminal kinases (JNKs) are ancient and evolutionarily conserved regulators of proliferation, differentiation, and cell death responses. Currently, in vitro studies offer conflicting data about whether the JNK pathway augments or represses osteoblast differentiation, and the contribution of the JNK pathway to regulation of bone mass in vivo remains unclear. Here we show that Jnk1–/– mice display severe osteopenia due to impaired bone formation, whereas Jnk2–/– mice display a mild osteopenia only evident in long bones. In order to both confirm that these effects were osteoblast intrinsic and assess whether redundancy with JNK1 masks a potential contribution of JNK2, mice with a conditional deletion of both JNK1 and JNK2 floxed conditional alleles in osteoblasts (Jnk1‐2osx) were bred. These mice displayed a similar degree of osteopenia to Jnk1–/– mice due to decreased bone formation. In vitro, Jnk1–/– osteoblasts display a selective defect in the late stages of osteoblast differentiation with impaired mineralization activity. Downstream of JNK1, phosphorylation of JUN is impaired in Jnk1–/– osteoblasts. Transcriptome analysis showed that JNK1 is required for upregulation of several osteoblast‐derived proangiogenic factors such as IGF2 and VEGFa. Accordingly, JNK1 deletion results in a significant reduction skeletal vasculature in mice. Taken together, this study establishes that JNK1 is a key mediator of osteoblast function in vivo and in vitro. © 2017 American Society for Bone and Mineral Research. |
doi_str_mv | 10.1002/jbmr.3184 |
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The c‐Jun N‐terminal kinases (JNKs) are ancient and evolutionarily conserved regulators of proliferation, differentiation, and cell death responses. Currently, in vitro studies offer conflicting data about whether the JNK pathway augments or represses osteoblast differentiation, and the contribution of the JNK pathway to regulation of bone mass in vivo remains unclear. Here we show that Jnk1–/– mice display severe osteopenia due to impaired bone formation, whereas Jnk2–/– mice display a mild osteopenia only evident in long bones. In order to both confirm that these effects were osteoblast intrinsic and assess whether redundancy with JNK1 masks a potential contribution of JNK2, mice with a conditional deletion of both JNK1 and JNK2 floxed conditional alleles in osteoblasts (Jnk1‐2osx) were bred. These mice displayed a similar degree of osteopenia to Jnk1–/– mice due to decreased bone formation. In vitro, Jnk1–/– osteoblasts display a selective defect in the late stages of osteoblast differentiation with impaired mineralization activity. Downstream of JNK1, phosphorylation of JUN is impaired in Jnk1–/– osteoblasts. Transcriptome analysis showed that JNK1 is required for upregulation of several osteoblast‐derived proangiogenic factors such as IGF2 and VEGFa. Accordingly, JNK1 deletion results in a significant reduction skeletal vasculature in mice. Taken together, this study establishes that JNK1 is a key mediator of osteoblast function in vivo and in vitro. © 2017 American Society for Bone and Mineral Research.</description><identifier>ISSN: 0884-0431</identifier><identifier>EISSN: 1523-4681</identifier><identifier>DOI: 10.1002/jbmr.3184</identifier><identifier>PMID: 28561373</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>ANGIOGENESIS ; Animals ; Bone Diseases, Metabolic - enzymology ; Bone Diseases, Metabolic - genetics ; Bone Diseases, Metabolic - pathology ; BONE FORMATION ; Bone growth ; Bone mass ; c-Jun protein ; Cell death ; Clonal deletion ; Gene expression ; Insulin-like growth factor II ; Insulin-Like Growth Factor II - genetics ; Insulin-Like Growth Factor II - metabolism ; JNK ; JNK protein ; JUN ; MAPK ; Mice ; Mice, Knockout ; Mineralization ; Mitogen-Activated Protein Kinase 8 - genetics ; Mitogen-Activated Protein Kinase 8 - metabolism ; Osteoblastogenesis ; OSTEOBLASTS ; Osteoblasts - enzymology ; Osteoblasts - pathology ; Osteogenesis ; Osteopenia ; Phosphorylation ; Transcription factors ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Journal of bone and mineral research, 2017-09, Vol.32 (9), p.1811-1815</ispartof><rights>2017 American Society for Bone and Mineral Research</rights><rights>2017 American Society for Bone and Mineral Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5094-935d61a21f2cec9ef59191cee608034f740f929ada66338c4cf56e331e22bfb83</citedby><cites>FETCH-LOGICAL-c5094-935d61a21f2cec9ef59191cee608034f740f929ada66338c4cf56e331e22bfb83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28561373$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Ren</creatorcontrib><creatorcontrib>Zhang, Chao</creatorcontrib><creatorcontrib>Shin, Dong Yeon</creatorcontrib><creatorcontrib>Kim, Jung‐Min</creatorcontrib><creatorcontrib>Lalani, Sarfaraz</creatorcontrib><creatorcontrib>Li, Na</creatorcontrib><creatorcontrib>Yang, Yeon‐Suk</creatorcontrib><creatorcontrib>Liu, Yifang</creatorcontrib><creatorcontrib>Eiseman, Mark</creatorcontrib><creatorcontrib>Davis, Roger J</creatorcontrib><creatorcontrib>Shim, Jae‐Hyuck</creatorcontrib><creatorcontrib>Greenblatt, Matthew B</creatorcontrib><title>c‐Jun N‐Terminal Kinases (JNKs) Are Critical Mediators of Osteoblast Activity In Vivo</title><title>Journal of bone and mineral research</title><addtitle>J Bone Miner Res</addtitle><description>ABSTRACT
The c‐Jun N‐terminal kinases (JNKs) are ancient and evolutionarily conserved regulators of proliferation, differentiation, and cell death responses. Currently, in vitro studies offer conflicting data about whether the JNK pathway augments or represses osteoblast differentiation, and the contribution of the JNK pathway to regulation of bone mass in vivo remains unclear. Here we show that Jnk1–/– mice display severe osteopenia due to impaired bone formation, whereas Jnk2–/– mice display a mild osteopenia only evident in long bones. In order to both confirm that these effects were osteoblast intrinsic and assess whether redundancy with JNK1 masks a potential contribution of JNK2, mice with a conditional deletion of both JNK1 and JNK2 floxed conditional alleles in osteoblasts (Jnk1‐2osx) were bred. These mice displayed a similar degree of osteopenia to Jnk1–/– mice due to decreased bone formation. In vitro, Jnk1–/– osteoblasts display a selective defect in the late stages of osteoblast differentiation with impaired mineralization activity. Downstream of JNK1, phosphorylation of JUN is impaired in Jnk1–/– osteoblasts. Transcriptome analysis showed that JNK1 is required for upregulation of several osteoblast‐derived proangiogenic factors such as IGF2 and VEGFa. Accordingly, JNK1 deletion results in a significant reduction skeletal vasculature in mice. Taken together, this study establishes that JNK1 is a key mediator of osteoblast function in vivo and in vitro. © 2017 American Society for Bone and Mineral Research.</description><subject>ANGIOGENESIS</subject><subject>Animals</subject><subject>Bone Diseases, Metabolic - enzymology</subject><subject>Bone Diseases, Metabolic - genetics</subject><subject>Bone Diseases, Metabolic - pathology</subject><subject>BONE FORMATION</subject><subject>Bone growth</subject><subject>Bone mass</subject><subject>c-Jun protein</subject><subject>Cell death</subject><subject>Clonal deletion</subject><subject>Gene expression</subject><subject>Insulin-like growth factor II</subject><subject>Insulin-Like Growth Factor II - genetics</subject><subject>Insulin-Like Growth Factor II - metabolism</subject><subject>JNK</subject><subject>JNK protein</subject><subject>JUN</subject><subject>MAPK</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mineralization</subject><subject>Mitogen-Activated Protein Kinase 8 - genetics</subject><subject>Mitogen-Activated Protein Kinase 8 - metabolism</subject><subject>Osteoblastogenesis</subject><subject>OSTEOBLASTS</subject><subject>Osteoblasts - enzymology</subject><subject>Osteoblasts - pathology</subject><subject>Osteogenesis</subject><subject>Osteopenia</subject><subject>Phosphorylation</subject><subject>Transcription factors</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>0884-0431</issn><issn>1523-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp1kctu1DAUhi1ERYfCghdAlti0i7S-xWNvkIYRhU5vEipIrCzHcwIeJXGxk6lmxyP0GfskOJ1SARKbcxbn06df50foFSWHlBB2tKraeMipEk_QhJaMF0Iq-hRNiFKiIILTXfQ8pRUhRJZSPkO7TJWS8imfoK_u7uftYujwRd5XEFvf2Qaf5pkg4f3FxWk6wLMIeB59712-ncPS2z7EhEONL1MPoWps6vHM9X7t-w0-6fAXvw4v0E5tmwQvH_Ye-nz8_mr-sTi7_HAyn50VriRaFJqXS0ktozVz4DTUpaaaOgBJFOGingpSa6bt0krJuXLC1aUEzikwVtWV4nvo7dZ7PVQtLB10fbSNuY6-tXFjgvXm70vnv5tvYW3KUms6HQX7D4IYfgyQetP65KBpbAdhSIZqIlj-mGAZffMPugpDzB8bKaZyPqV5pg62lIshpQj1YxhKzFiYGQszY2GZff1n-kfyd0MZONoCN76Bzf9NZvHu_NO98hebgaEr</recordid><startdate>201709</startdate><enddate>201709</enddate><creator>Xu, Ren</creator><creator>Zhang, Chao</creator><creator>Shin, Dong Yeon</creator><creator>Kim, Jung‐Min</creator><creator>Lalani, Sarfaraz</creator><creator>Li, Na</creator><creator>Yang, Yeon‐Suk</creator><creator>Liu, Yifang</creator><creator>Eiseman, Mark</creator><creator>Davis, Roger J</creator><creator>Shim, Jae‐Hyuck</creator><creator>Greenblatt, Matthew B</creator><general>Wiley Subscription Services, Inc</general><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>7TS</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201709</creationdate><title>c‐Jun N‐Terminal Kinases (JNKs) Are Critical Mediators of Osteoblast Activity In Vivo</title><author>Xu, Ren ; Zhang, Chao ; Shin, Dong Yeon ; Kim, Jung‐Min ; Lalani, Sarfaraz ; Li, Na ; Yang, Yeon‐Suk ; Liu, Yifang ; Eiseman, Mark ; Davis, Roger J ; Shim, Jae‐Hyuck ; Greenblatt, Matthew B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5094-935d61a21f2cec9ef59191cee608034f740f929ada66338c4cf56e331e22bfb83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>ANGIOGENESIS</topic><topic>Animals</topic><topic>Bone Diseases, Metabolic - enzymology</topic><topic>Bone Diseases, Metabolic - genetics</topic><topic>Bone Diseases, Metabolic - pathology</topic><topic>BONE FORMATION</topic><topic>Bone growth</topic><topic>Bone mass</topic><topic>c-Jun protein</topic><topic>Cell death</topic><topic>Clonal deletion</topic><topic>Gene expression</topic><topic>Insulin-like growth factor II</topic><topic>Insulin-Like Growth Factor II - genetics</topic><topic>Insulin-Like Growth Factor II - metabolism</topic><topic>JNK</topic><topic>JNK protein</topic><topic>JUN</topic><topic>MAPK</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mineralization</topic><topic>Mitogen-Activated Protein Kinase 8 - genetics</topic><topic>Mitogen-Activated Protein Kinase 8 - metabolism</topic><topic>Osteoblastogenesis</topic><topic>OSTEOBLASTS</topic><topic>Osteoblasts - enzymology</topic><topic>Osteoblasts - pathology</topic><topic>Osteogenesis</topic><topic>Osteopenia</topic><topic>Phosphorylation</topic><topic>Transcription factors</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Ren</creatorcontrib><creatorcontrib>Zhang, Chao</creatorcontrib><creatorcontrib>Shin, Dong Yeon</creatorcontrib><creatorcontrib>Kim, Jung‐Min</creatorcontrib><creatorcontrib>Lalani, Sarfaraz</creatorcontrib><creatorcontrib>Li, Na</creatorcontrib><creatorcontrib>Yang, Yeon‐Suk</creatorcontrib><creatorcontrib>Liu, Yifang</creatorcontrib><creatorcontrib>Eiseman, Mark</creatorcontrib><creatorcontrib>Davis, Roger J</creatorcontrib><creatorcontrib>Shim, Jae‐Hyuck</creatorcontrib><creatorcontrib>Greenblatt, Matthew B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of bone and mineral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Ren</au><au>Zhang, Chao</au><au>Shin, Dong Yeon</au><au>Kim, Jung‐Min</au><au>Lalani, Sarfaraz</au><au>Li, Na</au><au>Yang, Yeon‐Suk</au><au>Liu, Yifang</au><au>Eiseman, Mark</au><au>Davis, Roger J</au><au>Shim, Jae‐Hyuck</au><au>Greenblatt, Matthew B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>c‐Jun N‐Terminal Kinases (JNKs) Are Critical Mediators of Osteoblast Activity In Vivo</atitle><jtitle>Journal of bone and mineral research</jtitle><addtitle>J Bone Miner Res</addtitle><date>2017-09</date><risdate>2017</risdate><volume>32</volume><issue>9</issue><spage>1811</spage><epage>1815</epage><pages>1811-1815</pages><issn>0884-0431</issn><eissn>1523-4681</eissn><abstract>ABSTRACT
The c‐Jun N‐terminal kinases (JNKs) are ancient and evolutionarily conserved regulators of proliferation, differentiation, and cell death responses. Currently, in vitro studies offer conflicting data about whether the JNK pathway augments or represses osteoblast differentiation, and the contribution of the JNK pathway to regulation of bone mass in vivo remains unclear. Here we show that Jnk1–/– mice display severe osteopenia due to impaired bone formation, whereas Jnk2–/– mice display a mild osteopenia only evident in long bones. In order to both confirm that these effects were osteoblast intrinsic and assess whether redundancy with JNK1 masks a potential contribution of JNK2, mice with a conditional deletion of both JNK1 and JNK2 floxed conditional alleles in osteoblasts (Jnk1‐2osx) were bred. These mice displayed a similar degree of osteopenia to Jnk1–/– mice due to decreased bone formation. In vitro, Jnk1–/– osteoblasts display a selective defect in the late stages of osteoblast differentiation with impaired mineralization activity. Downstream of JNK1, phosphorylation of JUN is impaired in Jnk1–/– osteoblasts. Transcriptome analysis showed that JNK1 is required for upregulation of several osteoblast‐derived proangiogenic factors such as IGF2 and VEGFa. Accordingly, JNK1 deletion results in a significant reduction skeletal vasculature in mice. Taken together, this study establishes that JNK1 is a key mediator of osteoblast function in vivo and in vitro. © 2017 American Society for Bone and Mineral Research.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28561373</pmid><doi>10.1002/jbmr.3184</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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subjects | ANGIOGENESIS Animals Bone Diseases, Metabolic - enzymology Bone Diseases, Metabolic - genetics Bone Diseases, Metabolic - pathology BONE FORMATION Bone growth Bone mass c-Jun protein Cell death Clonal deletion Gene expression Insulin-like growth factor II Insulin-Like Growth Factor II - genetics Insulin-Like Growth Factor II - metabolism JNK JNK protein JUN MAPK Mice Mice, Knockout Mineralization Mitogen-Activated Protein Kinase 8 - genetics Mitogen-Activated Protein Kinase 8 - metabolism Osteoblastogenesis OSTEOBLASTS Osteoblasts - enzymology Osteoblasts - pathology Osteogenesis Osteopenia Phosphorylation Transcription factors Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism |
title | c‐Jun N‐Terminal Kinases (JNKs) Are Critical Mediators of Osteoblast Activity In Vivo |
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