TGF-Beta Negatively Regulates the BMP2-Dependent Early Commitment of Periodontal Ligament Cells into Hard Tissue Forming Cells
Transforming growth factor beta (TGF-β) is a multi-functional growth factor expressed in many tissues and organs. Genetic animal models have revealed the critical functions of TGF-β in craniofacial development, including the teeth and periodontal tissue. However, the physiological function of TGF-β...
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| description | Transforming growth factor beta (TGF-β) is a multi-functional growth factor expressed in many tissues and organs. Genetic animal models have revealed the critical functions of TGF-β in craniofacial development, including the teeth and periodontal tissue. However, the physiological function of TGF-β in the periodontal ligament (PDL) has not been fully elucidated. In this study, we examined the roles of TGF-β in the cytodifferentiation of PDL cells using a TGF-β receptor kinase inhibitor, SB431542. Mouse PDL cell clones (MPDL22) were cultured in calcification-inducing medium with or without SB431542 in the presence or absence of various growth factors, such as bone morphogenetic protein (BMP)-2, TGF-β and fibroblast growth factor (FGF)-2. SB431542 dramatically enhanced the BMP-2-dependent calcification of MPDL22 cells and accelerated the expression of ossification genes alkaline phosphatase (ALPase) and Runt-related transcription factor (Runx) 2 during early osteoblastic differentiation. SB431542 did not promote MPDL22 calcification without BMP-2 stimulation. The cell growth rate and collagen synthesis during the late stage of MPDL22 culture were retarded by SB431542. Quantitative reverse transcription polymerase chain reaction analysis revealed that the expressions of Smurf1 and Smad6, which are negative feedback components in the TGF-β/BMP signaling pathway, were downregulated in MPDL22 cells with SB431542 treatment. These results suggest that an endogenous signal from TGF-β negatively regulates the early commitment and cytodifferentiation of PDL cells into hard tissue-forming cells. A synthetic drug that regulates endogenous TGF-β signals may be efficacious for developing periodontal regenerative therapies. |
| doi_str_mv | 10.1371/journal.pone.0125590 |
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Genetic animal models have revealed the critical functions of TGF-β in craniofacial development, including the teeth and periodontal tissue. However, the physiological function of TGF-β in the periodontal ligament (PDL) has not been fully elucidated. In this study, we examined the roles of TGF-β in the cytodifferentiation of PDL cells using a TGF-β receptor kinase inhibitor, SB431542. Mouse PDL cell clones (MPDL22) were cultured in calcification-inducing medium with or without SB431542 in the presence or absence of various growth factors, such as bone morphogenetic protein (BMP)-2, TGF-β and fibroblast growth factor (FGF)-2. SB431542 dramatically enhanced the BMP-2-dependent calcification of MPDL22 cells and accelerated the expression of ossification genes alkaline phosphatase (ALPase) and Runt-related transcription factor (Runx) 2 during early osteoblastic differentiation. SB431542 did not promote MPDL22 calcification without BMP-2 stimulation. The cell growth rate and collagen synthesis during the late stage of MPDL22 culture were retarded by SB431542. Quantitative reverse transcription polymerase chain reaction analysis revealed that the expressions of Smurf1 and Smad6, which are negative feedback components in the TGF-β/BMP signaling pathway, were downregulated in MPDL22 cells with SB431542 treatment. These results suggest that an endogenous signal from TGF-β negatively regulates the early commitment and cytodifferentiation of PDL cells into hard tissue-forming cells. A synthetic drug that regulates endogenous TGF-β signals may be efficacious for developing periodontal regenerative therapies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0125590</identifier><identifier>PMID: 25970290</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alkaline phosphatase ; Animal models ; Animals ; Benzamides - pharmacology ; Biocompatibility ; Biomedical materials ; Bone growth ; Bone morphogenetic protein 2 ; Bone Morphogenetic Protein 2 - physiology ; Bone morphogenetic proteins ; Calcification ; Cell culture ; Cell Differentiation ; Cell Line ; Cell Proliferation ; Collagen ; Craniofacial growth ; Cytokines ; Dentistry ; Dioxoles - pharmacology ; Drug Evaluation, Preclinical ; Enzyme inhibitors ; Extracellular matrix ; Fibroblasts ; Forming ; Gene expression ; Genetic aspects ; Growth factors ; Growth rate ; Humans ; Kinases ; Ligaments ; Mice, Inbred BALB C ; Negative feedback ; Organs ; Ossification ; Osteoblastogenesis ; Osteoblasts ; Periodontal ligament ; Periodontal Ligament - cytology ; Physiological aspects ; Polymerase chain reaction ; Proteins ; Reverse transcription ; Signal transduction ; Signaling ; Stem cells ; Teeth ; Tissues ; Transforming Growth Factor beta - physiology ; Transforming growth factor-a ; Transforming growth factor-b ; Transforming growth factors</subject><ispartof>PloS one, 2015-05, Vol.10 (5), p.e0125590-e0125590</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Kawahara 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>2015 Kawahara et al 2015 Kawahara et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c622t-335e7ca7b5dbc78a403b8501c8c661bb48933aa2a0ebba9ba9704922a5ae89873</citedby><cites>FETCH-LOGICAL-c622t-335e7ca7b5dbc78a403b8501c8c661bb48933aa2a0ebba9ba9704922a5ae89873</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/PMC4430433/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430433/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25970290$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Genetos, Damian Christopher</contributor><creatorcontrib>Kawahara, Takanobu</creatorcontrib><creatorcontrib>Yamashita, Motozo</creatorcontrib><creatorcontrib>Ikegami, Kuniko</creatorcontrib><creatorcontrib>Nakamura, Tomomi</creatorcontrib><creatorcontrib>Yanagita, Manabu</creatorcontrib><creatorcontrib>Yamada, Satoru</creatorcontrib><creatorcontrib>Kitamura, Masahiro</creatorcontrib><creatorcontrib>Murakami, Shinya</creatorcontrib><title>TGF-Beta Negatively Regulates the BMP2-Dependent Early Commitment of Periodontal Ligament Cells into Hard Tissue Forming Cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Transforming growth factor beta (TGF-β) is a multi-functional growth factor expressed in many tissues and organs. Genetic animal models have revealed the critical functions of TGF-β in craniofacial development, including the teeth and periodontal tissue. However, the physiological function of TGF-β in the periodontal ligament (PDL) has not been fully elucidated. In this study, we examined the roles of TGF-β in the cytodifferentiation of PDL cells using a TGF-β receptor kinase inhibitor, SB431542. Mouse PDL cell clones (MPDL22) were cultured in calcification-inducing medium with or without SB431542 in the presence or absence of various growth factors, such as bone morphogenetic protein (BMP)-2, TGF-β and fibroblast growth factor (FGF)-2. SB431542 dramatically enhanced the BMP-2-dependent calcification of MPDL22 cells and accelerated the expression of ossification genes alkaline phosphatase (ALPase) and Runt-related transcription factor (Runx) 2 during early osteoblastic differentiation. SB431542 did not promote MPDL22 calcification without BMP-2 stimulation. The cell growth rate and collagen synthesis during the late stage of MPDL22 culture were retarded by SB431542. Quantitative reverse transcription polymerase chain reaction analysis revealed that the expressions of Smurf1 and Smad6, which are negative feedback components in the TGF-β/BMP signaling pathway, were downregulated in MPDL22 cells with SB431542 treatment. These results suggest that an endogenous signal from TGF-β negatively regulates the early commitment and cytodifferentiation of PDL cells into hard tissue-forming cells. A synthetic drug that regulates endogenous TGF-β signals may be efficacious for developing periodontal regenerative therapies.</description><subject>Alkaline phosphatase</subject><subject>Animal models</subject><subject>Animals</subject><subject>Benzamides - pharmacology</subject><subject>Biocompatibility</subject><subject>Biomedical materials</subject><subject>Bone growth</subject><subject>Bone morphogenetic protein 2</subject><subject>Bone Morphogenetic Protein 2 - physiology</subject><subject>Bone morphogenetic proteins</subject><subject>Calcification</subject><subject>Cell culture</subject><subject>Cell Differentiation</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Collagen</subject><subject>Craniofacial growth</subject><subject>Cytokines</subject><subject>Dentistry</subject><subject>Dioxoles - pharmacology</subject><subject>Drug Evaluation, Preclinical</subject><subject>Enzyme inhibitors</subject><subject>Extracellular matrix</subject><subject>Fibroblasts</subject><subject>Forming</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Growth factors</subject><subject>Growth rate</subject><subject>Humans</subject><subject>Kinases</subject><subject>Ligaments</subject><subject>Mice, Inbred BALB C</subject><subject>Negative feedback</subject><subject>Organs</subject><subject>Ossification</subject><subject>Osteoblastogenesis</subject><subject>Osteoblasts</subject><subject>Periodontal ligament</subject><subject>Periodontal Ligament - cytology</subject><subject>Physiological aspects</subject><subject>Polymerase chain reaction</subject><subject>Proteins</subject><subject>Reverse transcription</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Stem cells</subject><subject>Teeth</subject><subject>Tissues</subject><subject>Transforming Growth Factor beta - physiology</subject><subject>Transforming growth factor-a</subject><subject>Transforming growth factor-b</subject><subject>Transforming growth factors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYmPwDxBEQkJw0eKPJE5ukLaybpUKm0bh1jpJTlJXSVxsZ2I3_HactptatAtkS7aOn_Pafu0TBK8pGVMu6KeV7k0HzXitOxwTyuI4I0-CY5pxNkoY4U_35kfBC2tXhMQ8TZLnwRGLM0FYRo6DP4uL6egMHYTfsAanbrG5C2-w7htwaEO3xPDs6zUbfcE1diV2LjwH45GJblvl2iGgq_AajdKl7hw04VzVsIlPsGlsqDqnw0swZbhQ1vYYTrVpVVdvl18GzypoLL7ajSfBj-n5YnI5ml9dzCan81GRMOZGnMcoChB5XOaFSCEiPE9jQou0SBKa51GacQ7AgGCeQ-a7IFHGGMSAaZYKfhK83equG23lzjoraZISQZJMDMRsS5QaVnJtVAvmTmpQchPQppZgnCoalJUohYDKn4YkEU3LjFWRfwBRRpClCcRe6_Nutz5vsSy8GwaaA9HDlU4tZa1vZRRxEnHuBT7sBIz-1aN1slW28IZBh7rfnJuyxMMD-u4f9PHb7aga_AVUV2m_bzGIytOIM0IjnlBPjR-hfCuxVYX_Z5Xy8YOEjwcJnnH429XQWytn32_-n736eci-32OXCI1bWt30TunOHoLRFiyMttZg9WAyJXIok3s35FAmclcmPu3N_gM9JN3XBf8LlFML_Q</recordid><startdate>20150513</startdate><enddate>20150513</enddate><creator>Kawahara, Takanobu</creator><creator>Yamashita, Motozo</creator><creator>Ikegami, Kuniko</creator><creator>Nakamura, Tomomi</creator><creator>Yanagita, Manabu</creator><creator>Yamada, Satoru</creator><creator>Kitamura, Masahiro</creator><creator>Murakami, Shinya</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150513</creationdate><title>TGF-Beta Negatively Regulates the BMP2-Dependent Early Commitment of Periodontal Ligament Cells into Hard Tissue Forming Cells</title><author>Kawahara, Takanobu ; Yamashita, Motozo ; Ikegami, Kuniko ; Nakamura, Tomomi ; Yanagita, Manabu ; Yamada, Satoru ; Kitamura, Masahiro ; Murakami, Shinya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c622t-335e7ca7b5dbc78a403b8501c8c661bb48933aa2a0ebba9ba9704922a5ae89873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alkaline phosphatase</topic><topic>Animal models</topic><topic>Animals</topic><topic>Benzamides - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kawahara, Takanobu</au><au>Yamashita, Motozo</au><au>Ikegami, Kuniko</au><au>Nakamura, Tomomi</au><au>Yanagita, Manabu</au><au>Yamada, Satoru</au><au>Kitamura, Masahiro</au><au>Murakami, Shinya</au><au>Genetos, Damian Christopher</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TGF-Beta Negatively Regulates the BMP2-Dependent Early Commitment of Periodontal Ligament Cells into Hard Tissue Forming Cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-05-13</date><risdate>2015</risdate><volume>10</volume><issue>5</issue><spage>e0125590</spage><epage>e0125590</epage><pages>e0125590-e0125590</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Transforming growth factor beta (TGF-β) is a multi-functional growth factor expressed in many tissues and organs. Genetic animal models have revealed the critical functions of TGF-β in craniofacial development, including the teeth and periodontal tissue. However, the physiological function of TGF-β in the periodontal ligament (PDL) has not been fully elucidated. In this study, we examined the roles of TGF-β in the cytodifferentiation of PDL cells using a TGF-β receptor kinase inhibitor, SB431542. Mouse PDL cell clones (MPDL22) were cultured in calcification-inducing medium with or without SB431542 in the presence or absence of various growth factors, such as bone morphogenetic protein (BMP)-2, TGF-β and fibroblast growth factor (FGF)-2. SB431542 dramatically enhanced the BMP-2-dependent calcification of MPDL22 cells and accelerated the expression of ossification genes alkaline phosphatase (ALPase) and Runt-related transcription factor (Runx) 2 during early osteoblastic differentiation. SB431542 did not promote MPDL22 calcification without BMP-2 stimulation. The cell growth rate and collagen synthesis during the late stage of MPDL22 culture were retarded by SB431542. Quantitative reverse transcription polymerase chain reaction analysis revealed that the expressions of Smurf1 and Smad6, which are negative feedback components in the TGF-β/BMP signaling pathway, were downregulated in MPDL22 cells with SB431542 treatment. These results suggest that an endogenous signal from TGF-β negatively regulates the early commitment and cytodifferentiation of PDL cells into hard tissue-forming cells. A synthetic drug that regulates endogenous TGF-β signals may be efficacious for developing periodontal regenerative therapies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25970290</pmid><doi>10.1371/journal.pone.0125590</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1680706977 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alkaline phosphatase Animal models Animals Benzamides - pharmacology Biocompatibility Biomedical materials Bone growth Bone morphogenetic protein 2 Bone Morphogenetic Protein 2 - physiology Bone morphogenetic proteins Calcification Cell culture Cell Differentiation Cell Line Cell Proliferation Collagen Craniofacial growth Cytokines Dentistry Dioxoles - pharmacology Drug Evaluation, Preclinical Enzyme inhibitors Extracellular matrix Fibroblasts Forming Gene expression Genetic aspects Growth factors Growth rate Humans Kinases Ligaments Mice, Inbred BALB C Negative feedback Organs Ossification Osteoblastogenesis Osteoblasts Periodontal ligament Periodontal Ligament - cytology Physiological aspects Polymerase chain reaction Proteins Reverse transcription Signal transduction Signaling Stem cells Teeth Tissues Transforming Growth Factor beta - physiology Transforming growth factor-a Transforming growth factor-b Transforming growth factors |
| title | TGF-Beta Negatively Regulates the BMP2-Dependent Early Commitment of Periodontal Ligament Cells into Hard Tissue Forming Cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T13%3A53%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TGF-Beta%20Negatively%20Regulates%20the%20BMP2-Dependent%20Early%20Commitment%20of%20Periodontal%20Ligament%20Cells%20into%20Hard%20Tissue%20Forming%20Cells&rft.jtitle=PloS%20one&rft.au=Kawahara,%20Takanobu&rft.date=2015-05-13&rft.volume=10&rft.issue=5&rft.spage=e0125590&rft.epage=e0125590&rft.pages=e0125590-e0125590&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0125590&rft_dat=%3Cgale_plos_%3EA432014361%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1680706977&rft_id=info:pmid/25970290&rft_galeid=A432014361&rft_doaj_id=oai_doaj_org_article_f7d77af7b506418d92f40127d4a986a5&rfr_iscdi=true |