The calcium channel Orai1 is required for osteoblast development: Studies in a chimeric mouse with variable in vivo Runx-cre deletion of Orai-1
The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/f...
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| Veröffentlicht in: | PloS one 2023-05, Vol.18 (5), p.e0264596-e0264596 |
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| creator | Robinson, Lisa J Soboloff, Jonathan Tourkova, Irina L Larrouture, Quitterie C Onwuka, Kelechi M Papachristou, Dionysios J Gross, Scott Hooper, Robert Samakai, Elsie Worley, Paul F Liu, Peng Tuckermann, Jan Witt, Michelle R Blair, Harry C |
| description | The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1fl/fl) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1fl/fl-Runx2-cre bone. Specifically, antibody labeling for Orai1 in vertebral sections was uniform in wild type animals, but patchy regions in Orai1fl/fl-Runx2-cre bone revealed Orai1 loss while in other areas expression persisted. Nevertheless, by micro-CT, bones from Orai1fl/fl-Runx2-cre mice showed reduced bone mass overall, with impaired bone formation identified by dynamic histomorphometry. Cortical surfaces of Orai1fl/fl-Runx2-cre vertebrae however exhibited patchy defects. In cell culture, Orai1-negative osteoblasts showed profound reductions in store-operated Ca2+ entry, exhibited greatly decreased alkaline phosphatase activity, and had markedly impaired substrate mineralization. We conclude that defective bone formation observed in the absence of Orai1 reflects an intrinsic role for Orai1 in differentiating osteoblasts. |
| doi_str_mv | 10.1371/journal.pone.0264596 |
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To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1fl/fl) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1fl/fl-Runx2-cre bone. Specifically, antibody labeling for Orai1 in vertebral sections was uniform in wild type animals, but patchy regions in Orai1fl/fl-Runx2-cre bone revealed Orai1 loss while in other areas expression persisted. Nevertheless, by micro-CT, bones from Orai1fl/fl-Runx2-cre mice showed reduced bone mass overall, with impaired bone formation identified by dynamic histomorphometry. Cortical surfaces of Orai1fl/fl-Runx2-cre vertebrae however exhibited patchy defects. In cell culture, Orai1-negative osteoblasts showed profound reductions in store-operated Ca2+ entry, exhibited greatly decreased alkaline phosphatase activity, and had markedly impaired substrate mineralization. We conclude that defective bone formation observed in the absence of Orai1 reflects an intrinsic role for Orai1 in differentiating osteoblasts.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0264596</identifier><identifier>PMID: 37167218</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adipocytes ; Alkaline phosphatase ; Analysis ; Animals ; Antibodies ; Biology and Life Sciences ; Bone density ; Bone growth ; Bone histomorphometry ; Bone mass ; Bone resorption ; Bone turnover ; Bones ; Calcium ; Calcium - metabolism ; Calcium channels ; Calcium Channels - genetics ; Calcium Channels - metabolism ; Calcium influx ; Calcium ions ; Cbfa-1 protein ; Cell culture ; Cell differentiation ; Computed tomography ; Core Binding Factor Alpha 1 Subunit - genetics ; Core Binding Factor Alpha 1 Subunit - metabolism ; Defects ; Density ; Ethylenediaminetetraacetic acid ; Flox ; Health aspects ; Homeostasis ; In vivo methods and tests ; Ion channels ; Ions ; Labeling ; Medicine and Health Sciences ; Mice ; Mice, Knockout ; Mineralization ; Orai1 protein ; ORAI1 Protein - genetics ; ORAI1 Protein - metabolism ; Osteoblastogenesis ; Osteoblasts ; Osteoblasts - metabolism ; Osteogenesis ; Osteoprogenitor cells ; Penicillin ; Phosphatase ; Phosphatases ; Proteins ; Stem cells ; Substrates ; Tomography ; Vertebra ; Vertebrae ; Viral antibodies</subject><ispartof>PloS one, 2023-05, Vol.18 (5), p.e0264596-e0264596</ispartof><rights>Copyright: © 2023 Robinson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Robinson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Robinson et al 2023 Robinson et al</rights><rights>2023 Robinson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c693t-78d9766e07c0570451c12659ca85f947e3ec3c2523b7a840235384dbb82f0c7f3</citedby><cites>FETCH-LOGICAL-c693t-78d9766e07c0570451c12659ca85f947e3ec3c2523b7a840235384dbb82f0c7f3</cites><orcidid>0000-0001-9483-8346</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174572/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174572/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37167218$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Obukhov, Alexander G</contributor><creatorcontrib>Robinson, Lisa J</creatorcontrib><creatorcontrib>Soboloff, Jonathan</creatorcontrib><creatorcontrib>Tourkova, Irina L</creatorcontrib><creatorcontrib>Larrouture, Quitterie C</creatorcontrib><creatorcontrib>Onwuka, Kelechi M</creatorcontrib><creatorcontrib>Papachristou, Dionysios J</creatorcontrib><creatorcontrib>Gross, Scott</creatorcontrib><creatorcontrib>Hooper, Robert</creatorcontrib><creatorcontrib>Samakai, Elsie</creatorcontrib><creatorcontrib>Worley, Paul F</creatorcontrib><creatorcontrib>Liu, Peng</creatorcontrib><creatorcontrib>Tuckermann, Jan</creatorcontrib><creatorcontrib>Witt, Michelle R</creatorcontrib><creatorcontrib>Blair, Harry C</creatorcontrib><title>The calcium channel Orai1 is required for osteoblast development: Studies in a chimeric mouse with variable in vivo Runx-cre deletion of Orai-1</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1fl/fl) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1fl/fl-Runx2-cre bone. Specifically, antibody labeling for Orai1 in vertebral sections was uniform in wild type animals, but patchy regions in Orai1fl/fl-Runx2-cre bone revealed Orai1 loss while in other areas expression persisted. Nevertheless, by micro-CT, bones from Orai1fl/fl-Runx2-cre mice showed reduced bone mass overall, with impaired bone formation identified by dynamic histomorphometry. Cortical surfaces of Orai1fl/fl-Runx2-cre vertebrae however exhibited patchy defects. In cell culture, Orai1-negative osteoblasts showed profound reductions in store-operated Ca2+ entry, exhibited greatly decreased alkaline phosphatase activity, and had markedly impaired substrate mineralization. We conclude that defective bone formation observed in the absence of Orai1 reflects an intrinsic role for Orai1 in differentiating osteoblasts.</description><subject>Adipocytes</subject><subject>Alkaline phosphatase</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Biology and Life Sciences</subject><subject>Bone density</subject><subject>Bone growth</subject><subject>Bone histomorphometry</subject><subject>Bone mass</subject><subject>Bone resorption</subject><subject>Bone turnover</subject><subject>Bones</subject><subject>Calcium</subject><subject>Calcium - metabolism</subject><subject>Calcium channels</subject><subject>Calcium Channels - genetics</subject><subject>Calcium Channels - metabolism</subject><subject>Calcium influx</subject><subject>Calcium ions</subject><subject>Cbfa-1 protein</subject><subject>Cell culture</subject><subject>Cell differentiation</subject><subject>Computed tomography</subject><subject>Core Binding Factor Alpha 1 Subunit - genetics</subject><subject>Core Binding Factor Alpha 1 Subunit - metabolism</subject><subject>Defects</subject><subject>Density</subject><subject>Ethylenediaminetetraacetic acid</subject><subject>Flox</subject><subject>Health aspects</subject><subject>Homeostasis</subject><subject>In vivo methods and tests</subject><subject>Ion channels</subject><subject>Ions</subject><subject>Labeling</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mineralization</subject><subject>Orai1 protein</subject><subject>ORAI1 Protein - genetics</subject><subject>ORAI1 Protein - metabolism</subject><subject>Osteoblastogenesis</subject><subject>Osteoblasts</subject><subject>Osteoblasts - metabolism</subject><subject>Osteogenesis</subject><subject>Osteoprogenitor cells</subject><subject>Penicillin</subject><subject>Phosphatase</subject><subject>Phosphatases</subject><subject>Proteins</subject><subject>Stem 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one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robinson, Lisa J</au><au>Soboloff, Jonathan</au><au>Tourkova, Irina L</au><au>Larrouture, Quitterie C</au><au>Onwuka, Kelechi M</au><au>Papachristou, Dionysios J</au><au>Gross, Scott</au><au>Hooper, Robert</au><au>Samakai, Elsie</au><au>Worley, Paul F</au><au>Liu, Peng</au><au>Tuckermann, Jan</au><au>Witt, Michelle R</au><au>Blair, Harry C</au><au>Obukhov, Alexander G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The calcium channel Orai1 is required for osteoblast development: Studies in a chimeric mouse with variable in vivo Runx-cre deletion of Orai-1</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2023-05-11</date><risdate>2023</risdate><volume>18</volume><issue>5</issue><spage>e0264596</spage><epage>e0264596</epage><pages>e0264596-e0264596</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1fl/fl) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1fl/fl-Runx2-cre bone. Specifically, antibody labeling for Orai1 in vertebral sections was uniform in wild type animals, but patchy regions in Orai1fl/fl-Runx2-cre bone revealed Orai1 loss while in other areas expression persisted. Nevertheless, by micro-CT, bones from Orai1fl/fl-Runx2-cre mice showed reduced bone mass overall, with impaired bone formation identified by dynamic histomorphometry. Cortical surfaces of Orai1fl/fl-Runx2-cre vertebrae however exhibited patchy defects. In cell culture, Orai1-negative osteoblasts showed profound reductions in store-operated Ca2+ entry, exhibited greatly decreased alkaline phosphatase activity, and had markedly impaired substrate mineralization. We conclude that defective bone formation observed in the absence of Orai1 reflects an intrinsic role for Orai1 in differentiating osteoblasts.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>37167218</pmid><doi>10.1371/journal.pone.0264596</doi><tpages>e0264596</tpages><orcidid>https://orcid.org/0000-0001-9483-8346</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2023-05, Vol.18 (5), p.e0264596-e0264596 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2812421351 |
| source | MEDLINE; PubMed Central(OpenAccess); Public Library of Science; Full-Text Journals in Chemistry (Open access); DOAJ Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | Adipocytes Alkaline phosphatase Analysis Animals Antibodies Biology and Life Sciences Bone density Bone growth Bone histomorphometry Bone mass Bone resorption Bone turnover Bones Calcium Calcium - metabolism Calcium channels Calcium Channels - genetics Calcium Channels - metabolism Calcium influx Calcium ions Cbfa-1 protein Cell culture Cell differentiation Computed tomography Core Binding Factor Alpha 1 Subunit - genetics Core Binding Factor Alpha 1 Subunit - metabolism Defects Density Ethylenediaminetetraacetic acid Flox Health aspects Homeostasis In vivo methods and tests Ion channels Ions Labeling Medicine and Health Sciences Mice Mice, Knockout Mineralization Orai1 protein ORAI1 Protein - genetics ORAI1 Protein - metabolism Osteoblastogenesis Osteoblasts Osteoblasts - metabolism Osteogenesis Osteoprogenitor cells Penicillin Phosphatase Phosphatases Proteins Stem cells Substrates Tomography Vertebra Vertebrae Viral antibodies |
| title | The calcium channel Orai1 is required for osteoblast development: Studies in a chimeric mouse with variable in vivo Runx-cre deletion of Orai-1 |
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