Progranulin promotes diabetic fracture healing in mice with type 1 diabetes
Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor‐alpha is significantly upregulated in diabetic...
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| Veröffentlicht in: | Annals of the New York Academy of Sciences 2020-01, Vol.1460 (1), p.43-56 |
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| creator | Wei, Jianlu Zhang, Lei Ding, Yuanjing Liu, Ronghan Guo, Yuqi Hettinghouse, Aubryanna Buza, John De La Croix, Jean Li, Xin Einhorn, Thomas A. Liu, Chuan‐ju |
| description | Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor‐alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor‐like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN‐binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti‐inflammatory signaling pathways are involved in PGRN‐stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.
In this study, we employed wild‐type C57BL/6 and C57BL/6 background mice genetically modified for the absence of progranulin (PGRN) or tumor necrosis factor receptors and determined the role of endogenous and recombinant PGRN in diabetic fracture healing as well as the mechanism involved. |
| doi_str_mv | 10.1111/nyas.14208 |
| format | Article |
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In this study, we employed wild‐type C57BL/6 and C57BL/6 background mice genetically modified for the absence of progranulin (PGRN) or tumor necrosis factor receptors and determined the role of endogenous and recombinant PGRN in diabetic fracture healing as well as the mechanism involved.</description><identifier>ISSN: 0077-8923</identifier><identifier>EISSN: 1749-6632</identifier><identifier>DOI: 10.1111/nyas.14208</identifier><identifier>PMID: 31423598</identifier><language>eng</language><publisher>HOBOKEN: Wiley</publisher><subject>Animal models ; Animals ; Autoimmune diseases ; Binding ; Bone healing ; Chondrogenesis ; Chondrogenesis - drug effects ; Cytokines ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (insulin dependent) ; Diabetes Mellitus, Experimental - pathology ; Diabetes Mellitus, Type 1 - pathology ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Fracture Healing - drug effects ; Fractures ; Gene Deletion ; Genetic screening ; Growth factors ; Healing ; Health risks ; Humans ; impaired fracture healing ; In vivo methods and tests ; Inflammation ; Inflammation - pathology ; Insulin ; Mice ; Multidisciplinary Sciences ; progranulin ; Progranulins - deficiency ; Progranulins - pharmacology ; Proto-Oncogene Proteins c-akt - metabolism ; Receptors ; Receptors, Tumor Necrosis Factor - metabolism ; Recombinant Proteins - pharmacology ; Science & Technology ; Science & Technology - Other Topics ; Signal Transduction - drug effects ; TNFR1 ; TNFR2 ; TOR Serine-Threonine Kinases - metabolism ; Tumor necrosis factor ; Tumor necrosis factor receptors ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-TNF ; type 1 diabetes</subject><ispartof>Annals of the New York Academy of Sciences, 2020-01, Vol.1460 (1), p.43-56</ispartof><rights>2019 New York Academy of Sciences.</rights><rights>2020 The New York Academy of Sciences</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>15</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000481654400001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c4488-5414d3e23ca703b80617f9baeec376db4c6ab96c4716dc63b37ea9864d948ffe3</citedby><cites>FETCH-LOGICAL-c4488-5414d3e23ca703b80617f9baeec376db4c6ab96c4716dc63b37ea9864d948ffe3</cites><orcidid>0000-0002-7181-8032 ; 0000-0002-5075-4885 ; 0000-0003-1846-4375 ; 0000-0002-7414-5734 ; 0000-0002-6897-0279</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fnyas.14208$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fnyas.14208$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,781,785,886,1418,27929,27930,28253,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31423598$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wei, Jianlu</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Ding, Yuanjing</creatorcontrib><creatorcontrib>Liu, Ronghan</creatorcontrib><creatorcontrib>Guo, Yuqi</creatorcontrib><creatorcontrib>Hettinghouse, Aubryanna</creatorcontrib><creatorcontrib>Buza, John</creatorcontrib><creatorcontrib>De La Croix, Jean</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Einhorn, Thomas A.</creatorcontrib><creatorcontrib>Liu, Chuan‐ju</creatorcontrib><title>Progranulin promotes diabetic fracture healing in mice with type 1 diabetes</title><title>Annals of the New York Academy of Sciences</title><addtitle>ANN NY ACAD SCI</addtitle><addtitle>Ann N Y Acad Sci</addtitle><description>Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor‐alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor‐like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN‐binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti‐inflammatory signaling pathways are involved in PGRN‐stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.
In this study, we employed wild‐type C57BL/6 and C57BL/6 background mice genetically modified for the absence of progranulin (PGRN) or tumor necrosis factor receptors and determined the role of endogenous and recombinant PGRN in diabetic fracture healing as well as the mechanism involved.</description><subject>Animal models</subject><subject>Animals</subject><subject>Autoimmune diseases</subject><subject>Binding</subject><subject>Bone healing</subject><subject>Chondrogenesis</subject><subject>Chondrogenesis - drug effects</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetes Mellitus, Type 1 - pathology</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Fracture Healing - drug effects</subject><subject>Fractures</subject><subject>Gene Deletion</subject><subject>Genetic screening</subject><subject>Growth factors</subject><subject>Healing</subject><subject>Health risks</subject><subject>Humans</subject><subject>impaired fracture healing</subject><subject>In vivo methods and tests</subject><subject>Inflammation</subject><subject>Inflammation - pathology</subject><subject>Insulin</subject><subject>Mice</subject><subject>Multidisciplinary Sciences</subject><subject>progranulin</subject><subject>Progranulins - deficiency</subject><subject>Progranulins - pharmacology</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptors</subject><subject>Receptors, Tumor Necrosis Factor - metabolism</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Science & Technology</subject><subject>Science & Technology - Other Topics</subject><subject>Signal Transduction - drug effects</subject><subject>TNFR1</subject><subject>TNFR2</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tumor necrosis factor</subject><subject>Tumor necrosis factor receptors</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-TNF</subject><subject>type 1 diabetes</subject><issn>0077-8923</issn><issn>1749-6632</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><recordid>eNqN0EFPIyEYBmBiNFpdL_4AM4k3zSgMFJiLiWlW3WjUZHcPngjDfNNiWqjArOm_F2230YuRCyQ8fLx5ETog-JTkdeYWOp4SVmG5gQZEsLrknFabaICxEKWsK7qDdmN8wphUkolttEOzpsNaDtDNQ_DjoF0_ta6YBz_zCWLRWt1AsqbogjapD1BMQGcxLrKaWQPFi02TIi3mUJCVhvgDbXV6GmF_te-hv5c__4yuy9v7q1-ji9vSMCZlOWSEtRQqarTAtJGYE9HVjQYwVPC2YYbrpuaGCcJbw2lDBehactbWTHYd0D10vpw775sZtAZcCnqq5sHOdFgor636fOPsRI39PyUJlULUecDRakDwzz3EpJ58H1zOrCrKBB3mSCSr46UywccYoFv_QLB6K169Fa_ei8_48GOmNf3fdAZyCV6g8V00FpyBNcMYM0n4kLF8wmRkk07Wu5HvXcpPT77_NGuy0nYKiy8yq7vHi9_L9K93F7Ab</recordid><startdate>202001</startdate><enddate>202001</enddate><creator>Wei, Jianlu</creator><creator>Zhang, Lei</creator><creator>Ding, Yuanjing</creator><creator>Liu, Ronghan</creator><creator>Guo, Yuqi</creator><creator>Hettinghouse, Aubryanna</creator><creator>Buza, John</creator><creator>De La Croix, Jean</creator><creator>Li, Xin</creator><creator>Einhorn, Thomas A.</creator><creator>Liu, Chuan‐ju</creator><general>Wiley</general><general>Wiley Subscription Services, Inc</general><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7ST</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>SOI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7181-8032</orcidid><orcidid>https://orcid.org/0000-0002-5075-4885</orcidid><orcidid>https://orcid.org/0000-0003-1846-4375</orcidid><orcidid>https://orcid.org/0000-0002-7414-5734</orcidid><orcidid>https://orcid.org/0000-0002-6897-0279</orcidid></search><sort><creationdate>202001</creationdate><title>Progranulin promotes diabetic fracture healing in mice with type 1 diabetes</title><author>Wei, Jianlu ; Zhang, Lei ; Ding, Yuanjing ; Liu, Ronghan ; Guo, Yuqi ; Hettinghouse, Aubryanna ; Buza, John ; De La Croix, Jean ; Li, Xin ; Einhorn, Thomas A. ; Liu, Chuan‐ju</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4488-5414d3e23ca703b80617f9baeec376db4c6ab96c4716dc63b37ea9864d948ffe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Autoimmune diseases</topic><topic>Binding</topic><topic>Bone healing</topic><topic>Chondrogenesis</topic><topic>Chondrogenesis - drug effects</topic><topic>Cytokines</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetes Mellitus, Type 1 - pathology</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Fracture Healing - drug effects</topic><topic>Fractures</topic><topic>Gene Deletion</topic><topic>Genetic screening</topic><topic>Growth factors</topic><topic>Healing</topic><topic>Health risks</topic><topic>Humans</topic><topic>impaired fracture healing</topic><topic>In vivo methods and tests</topic><topic>Inflammation</topic><topic>Inflammation - pathology</topic><topic>Insulin</topic><topic>Mice</topic><topic>Multidisciplinary Sciences</topic><topic>progranulin</topic><topic>Progranulins - deficiency</topic><topic>Progranulins - pharmacology</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Receptors</topic><topic>Receptors, Tumor Necrosis Factor - metabolism</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Science & Technology</topic><topic>Science & Technology - Other Topics</topic><topic>Signal Transduction - drug effects</topic><topic>TNFR1</topic><topic>TNFR2</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Tumor necrosis factor</topic><topic>Tumor necrosis factor receptors</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-TNF</topic><topic>type 1 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wei, Jianlu</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Ding, Yuanjing</creatorcontrib><creatorcontrib>Liu, Ronghan</creatorcontrib><creatorcontrib>Guo, Yuqi</creatorcontrib><creatorcontrib>Hettinghouse, Aubryanna</creatorcontrib><creatorcontrib>Buza, John</creatorcontrib><creatorcontrib>De La Croix, Jean</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Einhorn, Thomas A.</creatorcontrib><creatorcontrib>Liu, Chuan‐ju</creatorcontrib><collection>Web of Science - 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Proinflammatory cytokine tumor necrosis factor‐alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor‐like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN‐binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti‐inflammatory signaling pathways are involved in PGRN‐stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.
In this study, we employed wild‐type C57BL/6 and C57BL/6 background mice genetically modified for the absence of progranulin (PGRN) or tumor necrosis factor receptors and determined the role of endogenous and recombinant PGRN in diabetic fracture healing as well as the mechanism involved.</abstract><cop>HOBOKEN</cop><pub>Wiley</pub><pmid>31423598</pmid><doi>10.1111/nyas.14208</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-7181-8032</orcidid><orcidid>https://orcid.org/0000-0002-5075-4885</orcidid><orcidid>https://orcid.org/0000-0003-1846-4375</orcidid><orcidid>https://orcid.org/0000-0002-7414-5734</orcidid><orcidid>https://orcid.org/0000-0002-6897-0279</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animal models Animals Autoimmune diseases Binding Bone healing Chondrogenesis Chondrogenesis - drug effects Cytokines Diabetes Diabetes mellitus Diabetes mellitus (insulin dependent) Diabetes Mellitus, Experimental - pathology Diabetes Mellitus, Type 1 - pathology Extracellular Signal-Regulated MAP Kinases - metabolism Fracture Healing - drug effects Fractures Gene Deletion Genetic screening Growth factors Healing Health risks Humans impaired fracture healing In vivo methods and tests Inflammation Inflammation - pathology Insulin Mice Multidisciplinary Sciences progranulin Progranulins - deficiency Progranulins - pharmacology Proto-Oncogene Proteins c-akt - metabolism Receptors Receptors, Tumor Necrosis Factor - metabolism Recombinant Proteins - pharmacology Science & Technology Science & Technology - Other Topics Signal Transduction - drug effects TNFR1 TNFR2 TOR Serine-Threonine Kinases - metabolism Tumor necrosis factor Tumor necrosis factor receptors Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF type 1 diabetes |
| title | Progranulin promotes diabetic fracture healing in mice with type 1 diabetes |
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