NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis
ROS are implicated in bone diseases. NADPH oxidase 4 (NOX4), a constitutively active enzymatic source of ROS, may contribute to the development of such disorders. Therefore, we studied the role of NOX4 in bone homeostasis. Nox4(-/-) mice displayed higher bone density and reduced numbers and markers...
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| Veröffentlicht in: | The Journal of clinical investigation 2013-11, Vol.123 (11), p.4731-4738 |
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| creator | Goettsch, Claudia Babelova, Andrea Trummer, Olivia Erben, Reinhold G Rauner, Martina Rammelt, Stefan Weissmann, Norbert Weinberger, Valeska Benkhoff, Sebastian Kampschulte, Marian Obermayer-Pietsch, Barbara Hofbauer, Lorenz C Brandes, Ralf P Schröder, Katrin |
| description | ROS are implicated in bone diseases. NADPH oxidase 4 (NOX4), a constitutively active enzymatic source of ROS, may contribute to the development of such disorders. Therefore, we studied the role of NOX4 in bone homeostasis. Nox4(-/-) mice displayed higher bone density and reduced numbers and markers of osteoclasts. Ex vivo, differentiation of monocytes into osteoclasts with RANKL and M-CSF induced Nox4 expression. Loss of NOX4 activity attenuated osteoclastogenesis, which was accompanied by impaired activation of RANKL-induced NFATc1 and c-JUN. In an in vivo model of murine ovariectomy–induced osteoporosis, pharmacological inhibition or acute genetic knockdown of Nox4 mitigated loss of trabecular bone. Human bone obtained from patients with increased osteoclast activity exhibited increased NOX4 expression. Moreover, a SNP of NOX4 was associated with elevated circulating markers of bone turnover and reduced bone density in women. Thus, NOX4 is involved in bone loss and represents a potential therapeutic target for the treatment of osteoporosis. |
| doi_str_mv | 10.1172/JCI67603 |
| format | Article |
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NADPH oxidase 4 (NOX4), a constitutively active enzymatic source of ROS, may contribute to the development of such disorders. Therefore, we studied the role of NOX4 in bone homeostasis. Nox4(-/-) mice displayed higher bone density and reduced numbers and markers of osteoclasts. Ex vivo, differentiation of monocytes into osteoclasts with RANKL and M-CSF induced Nox4 expression. Loss of NOX4 activity attenuated osteoclastogenesis, which was accompanied by impaired activation of RANKL-induced NFATc1 and c-JUN. In an in vivo model of murine ovariectomy–induced osteoporosis, pharmacological inhibition or acute genetic knockdown of Nox4 mitigated loss of trabecular bone. Human bone obtained from patients with increased osteoclast activity exhibited increased NOX4 expression. Moreover, a SNP of NOX4 was associated with elevated circulating markers of bone turnover and reduced bone density in women. Thus, NOX4 is involved in bone loss and represents a potential therapeutic target for the treatment of osteoporosis.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI67603</identifier><identifier>PMID: 24216508</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Animals ; Biomedical research ; Bone density ; Bone Density - genetics ; Bone Density - physiology ; Bone diseases ; Bone Resorption - genetics ; Bone Resorption - pathology ; Bone Resorption - physiopathology ; Bones ; Cell culture ; Cell Differentiation - genetics ; Cell Differentiation - physiology ; Colleges & universities ; Development and progression ; Disease Models, Animal ; Enzymes ; Female ; Genetic aspects ; Humans ; Macrophage Colony-Stimulating Factor - physiology ; Mice ; Mice, Knockout ; Middle Aged ; Monocytes - pathology ; Monocytes - physiology ; NADP (Coenzyme) ; NADPH Oxidase 4 ; NADPH Oxidases - deficiency ; NADPH Oxidases - genetics ; NADPH Oxidases - physiology ; Normal distribution ; Osteoclasts - pathology ; Osteoclasts - physiology ; Osteoporosis, Postmenopausal - genetics ; Osteoporosis, Postmenopausal - pathology ; Osteoporosis, Postmenopausal - physiopathology ; Oxidases ; Physiological aspects ; Polymorphism, Single Nucleotide ; RANK Ligand - physiology ; Reactive Oxygen Species - metabolism ; Risk factors</subject><ispartof>The Journal of clinical investigation, 2013-11, Vol.123 (11), p.4731-4738</ispartof><rights>COPYRIGHT 2013 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Nov 2013</rights><rights>Copyright © 2013, American Society for Clinical Investigation 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c676t-da4f237c5f79993f1168ae2f42900c6c56856c42d7fd5411e736bb251afe33693</citedby><cites>FETCH-LOGICAL-c676t-da4f237c5f79993f1168ae2f42900c6c56856c42d7fd5411e736bb251afe33693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809780/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809780/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24216508$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Goettsch, Claudia</creatorcontrib><creatorcontrib>Babelova, Andrea</creatorcontrib><creatorcontrib>Trummer, Olivia</creatorcontrib><creatorcontrib>Erben, Reinhold G</creatorcontrib><creatorcontrib>Rauner, Martina</creatorcontrib><creatorcontrib>Rammelt, Stefan</creatorcontrib><creatorcontrib>Weissmann, Norbert</creatorcontrib><creatorcontrib>Weinberger, Valeska</creatorcontrib><creatorcontrib>Benkhoff, Sebastian</creatorcontrib><creatorcontrib>Kampschulte, Marian</creatorcontrib><creatorcontrib>Obermayer-Pietsch, Barbara</creatorcontrib><creatorcontrib>Hofbauer, Lorenz C</creatorcontrib><creatorcontrib>Brandes, Ralf P</creatorcontrib><creatorcontrib>Schröder, Katrin</creatorcontrib><title>NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>ROS are implicated in bone diseases. NADPH oxidase 4 (NOX4), a constitutively active enzymatic source of ROS, may contribute to the development of such disorders. Therefore, we studied the role of NOX4 in bone homeostasis. Nox4(-/-) mice displayed higher bone density and reduced numbers and markers of osteoclasts. Ex vivo, differentiation of monocytes into osteoclasts with RANKL and M-CSF induced Nox4 expression. Loss of NOX4 activity attenuated osteoclastogenesis, which was accompanied by impaired activation of RANKL-induced NFATc1 and c-JUN. In an in vivo model of murine ovariectomy–induced osteoporosis, pharmacological inhibition or acute genetic knockdown of Nox4 mitigated loss of trabecular bone. Human bone obtained from patients with increased osteoclast activity exhibited increased NOX4 expression. Moreover, a SNP of NOX4 was associated with elevated circulating markers of bone turnover and reduced bone density in women. Thus, NOX4 is involved in bone loss and represents a potential therapeutic target for the treatment of osteoporosis.</description><subject>Animals</subject><subject>Biomedical research</subject><subject>Bone density</subject><subject>Bone Density - genetics</subject><subject>Bone Density - physiology</subject><subject>Bone diseases</subject><subject>Bone Resorption - genetics</subject><subject>Bone Resorption - pathology</subject><subject>Bone Resorption - physiopathology</subject><subject>Bones</subject><subject>Cell culture</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Differentiation - physiology</subject><subject>Colleges & universities</subject><subject>Development and progression</subject><subject>Disease Models, Animal</subject><subject>Enzymes</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Humans</subject><subject>Macrophage Colony-Stimulating Factor - physiology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Monocytes - pathology</subject><subject>Monocytes - physiology</subject><subject>NADP (Coenzyme)</subject><subject>NADPH Oxidase 4</subject><subject>NADPH Oxidases - deficiency</subject><subject>NADPH Oxidases - genetics</subject><subject>NADPH Oxidases - physiology</subject><subject>Normal distribution</subject><subject>Osteoclasts - pathology</subject><subject>Osteoclasts - physiology</subject><subject>Osteoporosis, Postmenopausal - genetics</subject><subject>Osteoporosis, Postmenopausal - pathology</subject><subject>Osteoporosis, Postmenopausal - physiopathology</subject><subject>Oxidases</subject><subject>Physiological aspects</subject><subject>Polymorphism, Single Nucleotide</subject><subject>RANK Ligand - physiology</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Risk factors</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkl1rFDEUhoModq2Cv0AGBNGLqfmezI24rB9dKVb8ug3ZzMlsysxknWSk_fdmcVu7shclFwnJc17evOcg9JTgE0Iq-vrTYikridk9NCNCqFJRpu6jGcaUlHXF1BF6FOMFxoRzwR-iI8opkQKrGXr7ef7uy2kRLn1jIhS86HzvUyxWYYCiNzGfrorNGPqQ_NAWISYItjMxhRYGiD4-Rg-c6SI82e3H6MeH998Xp-XZ-cflYn5W2uwslY3hjrLKClfVdc0cIVIZoI7TGmMrrZBKSMtpU7lGcEKgYnK1ooIYB4zJmh2jN391N9Oqh8bCkEbT6c3oezNe6WC83n8Z_Fq34bdmCteVwlng5U5gDL8miEn3PlroOjNAmKImAgvGKlbfAeU1Z5hStbX1_D_0IkzjkJPIlFQ5borZP6o1HWg_uJAt2q2onjMhmRBUqEyVB6htzvk_uR_O5-s9_uQAn1cDvbcHC17tFWQmwWVqzRSjXn77enf2_Oc---IWuwbTpXUM3ZR8GOI-uAvWjiHGEdxN_wjW20nW15Oc0We3-30DXo8u-wOkRect</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>Goettsch, Claudia</creator><creator>Babelova, Andrea</creator><creator>Trummer, Olivia</creator><creator>Erben, Reinhold G</creator><creator>Rauner, Martina</creator><creator>Rammelt, Stefan</creator><creator>Weissmann, Norbert</creator><creator>Weinberger, Valeska</creator><creator>Benkhoff, Sebastian</creator><creator>Kampschulte, Marian</creator><creator>Obermayer-Pietsch, Barbara</creator><creator>Hofbauer, Lorenz C</creator><creator>Brandes, Ralf P</creator><creator>Schröder, Katrin</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>7QP</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20131101</creationdate><title>NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis</title><author>Goettsch, Claudia ; Babelova, Andrea ; Trummer, Olivia ; Erben, Reinhold G ; Rauner, Martina ; Rammelt, Stefan ; Weissmann, Norbert ; Weinberger, Valeska ; Benkhoff, Sebastian ; Kampschulte, Marian ; Obermayer-Pietsch, Barbara ; Hofbauer, Lorenz C ; Brandes, Ralf P ; Schröder, Katrin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c676t-da4f237c5f79993f1168ae2f42900c6c56856c42d7fd5411e736bb251afe33693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Biomedical research</topic><topic>Bone density</topic><topic>Bone Density - 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NADPH oxidase 4 (NOX4), a constitutively active enzymatic source of ROS, may contribute to the development of such disorders. Therefore, we studied the role of NOX4 in bone homeostasis. Nox4(-/-) mice displayed higher bone density and reduced numbers and markers of osteoclasts. Ex vivo, differentiation of monocytes into osteoclasts with RANKL and M-CSF induced Nox4 expression. Loss of NOX4 activity attenuated osteoclastogenesis, which was accompanied by impaired activation of RANKL-induced NFATc1 and c-JUN. In an in vivo model of murine ovariectomy–induced osteoporosis, pharmacological inhibition or acute genetic knockdown of Nox4 mitigated loss of trabecular bone. Human bone obtained from patients with increased osteoclast activity exhibited increased NOX4 expression. Moreover, a SNP of NOX4 was associated with elevated circulating markers of bone turnover and reduced bone density in women. Thus, NOX4 is involved in bone loss and represents a potential therapeutic target for the treatment of osteoporosis.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>24216508</pmid><doi>10.1172/JCI67603</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Animals Biomedical research Bone density Bone Density - genetics Bone Density - physiology Bone diseases Bone Resorption - genetics Bone Resorption - pathology Bone Resorption - physiopathology Bones Cell culture Cell Differentiation - genetics Cell Differentiation - physiology Colleges & universities Development and progression Disease Models, Animal Enzymes Female Genetic aspects Humans Macrophage Colony-Stimulating Factor - physiology Mice Mice, Knockout Middle Aged Monocytes - pathology Monocytes - physiology NADP (Coenzyme) NADPH Oxidase 4 NADPH Oxidases - deficiency NADPH Oxidases - genetics NADPH Oxidases - physiology Normal distribution Osteoclasts - pathology Osteoclasts - physiology Osteoporosis, Postmenopausal - genetics Osteoporosis, Postmenopausal - pathology Osteoporosis, Postmenopausal - physiopathology Oxidases Physiological aspects Polymorphism, Single Nucleotide RANK Ligand - physiology Reactive Oxygen Species - metabolism Risk factors |
| title | NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis |
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