High-throughput micro-CT analysis identifies sex-dependent biomarkers of erosive arthritis in TNF-Tg mice and differential response to anti-TNF therapy
Development of reliable disease activity biomarkers is critical for diagnostics, prognostics, and novel drug development. Although computed tomography (CT) is the gold-standard for quantification of bone erosions, there are no consensus approaches or rationales for utilization of specific outcome me...
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| Veröffentlicht in: | PloS one 2024-07, Vol.19 (7), p.e0305623 |
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| creator | Kenney, H Mark Chen, Kiana L Schnur, Lindsay Fox, Jeffrey I Wood, Ronald W Xing, Lianping Ritchlin, Christopher T Rahimi, Homaira Schwarz, Edward M Awad, Hani A |
| description | Development of reliable disease activity biomarkers is critical for diagnostics, prognostics, and novel drug development. Although computed tomography (CT) is the gold-standard for quantification of bone erosions, there are no consensus approaches or rationales for utilization of specific outcome measures of erosive arthritis in complex joints. In the case of preclinical models, such as sexually dimorphic tumor necrosis factor transgenic (TNF-Tg) mice, disease severity is routinely quantified in the ankle through manual segmentation of the talus or small regions of adjacent bones primarily due to the ease in measurement. Herein, we sought to determine the particular hindpaw bones that represent reliable biomarkers of sex-dependent disease progression to guide future investigation and analysis.
Hindpaw micro-CT was performed on wild-type (n = 4 male, n = 4 female) and TNF-Tg (n = 4 male, n = 7 female) mice at monthly intervals from 2-5 (females) and 2-8-months (males) of age, since female TNF-Tg mice exhibit early mortality from cardiopulmonary disease at approximately 5-6-months. Further, 8-month-old WT (n = 4) and TNF-Tg males treated with anti-TNF monoclonal antibodies (n = 5) or IgG placebo isotype controls (n = 6) for 6-weeks were imaged with micro-CT every 3-weeks. For image analysis, we utilized our recently developed high-throughput and semi-automated segmentation strategy in Amira software. Synovial and osteoclast histology of ankle joints was quantified using Visiopharm.
First, we demonstrated that the accuracy of automated segmentation, determined through analysis of ~9000 individual bones by a single user, was comparable in wild-type and TNF-Tg hindpaws before correction (79.2±8.9% vs 80.1±5.1%, p = 0.52). Compared to other bone compartments, the tarsal region demonstrated a sudden, specific, and significant bone volume reduction in female TNF-Tg mice, but not in males, by 5-months (4-months 4.3± 0.22 vs 5-months 3.4± 0.62 mm3, p |
| doi_str_mv | 10.1371/journal.pone.0305623 |
| format | Article |
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Hindpaw micro-CT was performed on wild-type (n = 4 male, n = 4 female) and TNF-Tg (n = 4 male, n = 7 female) mice at monthly intervals from 2-5 (females) and 2-8-months (males) of age, since female TNF-Tg mice exhibit early mortality from cardiopulmonary disease at approximately 5-6-months. Further, 8-month-old WT (n = 4) and TNF-Tg males treated with anti-TNF monoclonal antibodies (n = 5) or IgG placebo isotype controls (n = 6) for 6-weeks were imaged with micro-CT every 3-weeks. For image analysis, we utilized our recently developed high-throughput and semi-automated segmentation strategy in Amira software. Synovial and osteoclast histology of ankle joints was quantified using Visiopharm.
First, we demonstrated that the accuracy of automated segmentation, determined through analysis of ~9000 individual bones by a single user, was comparable in wild-type and TNF-Tg hindpaws before correction (79.2±8.9% vs 80.1±5.1%, p = 0.52). Compared to other bone compartments, the tarsal region demonstrated a sudden, specific, and significant bone volume reduction in female TNF-Tg mice, but not in males, by 5-months (4-months 4.3± 0.22 vs 5-months 3.4± 0.62 mm3, p<0.05). Specifically, the cuboid showed significantly reduced bone volumes at early timepoints compared to other tarsals (i.e., 4-months: Cuboid -24.1±7.2% vs Talus -9.0±5.9% of 2-month baseline). Additional bones localized to the anterolateral region of the ankle also exhibited dramatic erosions in the tarsal region of females, coinciding with increased synovitis and osteoclasts. In TNF-Tg male mice with severe arthritis, the talus and calcaneus exhibited the most sensitive response to anti-TNF therapy measured by effect size of bone volume change over treatment period.
We demonstrated that sexually dimorphic changes in arthritic hindpaws of TNF-Tg mice are bone-specific, where the cuboid serves as a reliable early biomarker of erosive arthritis in female mice. Adoption of automated segmentation approaches in pre-clinical or clinical models has potential to translate quantitative biomarkers to monitor bone erosions in disease and evaluate therapeutic efficacy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0305623</identifier><identifier>PMID: 38968295</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal models ; Animals ; Ankle ; Arthritis ; Biological markers ; Biology and Life Sciences ; Biomarkers ; Bone density ; Bones ; Calcaneus ; Computed tomography ; CT imaging ; Disease Models, Animal ; Diseases ; Drug development ; Effectiveness ; Engineering and Technology ; Female ; Females ; Genetic engineering ; Health aspects ; Histology ; Image analysis ; Image processing ; Immunoglobulin G ; Inflammation ; Joint diseases ; Joints (anatomy) ; Magnetic resonance imaging ; Male ; Males ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Monoclonal antibodies ; Osteoclasts ; Pathogenesis ; Research and Analysis Methods ; Segmentation ; Sex Characteristics ; Sex Factors ; Sexual dimorphism ; Soil erosion ; Synovitis ; Talus ; Transgenic mice ; Tumor necrosis factor ; Tumor Necrosis Factor-alpha - antagonists & inhibitors ; X-Ray Microtomography - methods</subject><ispartof>PloS one, 2024-07, Vol.19 (7), p.e0305623</ispartof><rights>Copyright: © 2024 Kenney 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 2024 Public Library of Science</rights><rights>2024 Kenney 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>2024 Kenney et al 2024 Kenney et al</rights><rights>2024 Kenney 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><cites>FETCH-LOGICAL-c642t-d1f6463e685a9bfce9d35d521b1a6625f963ce488e20c85c4aea9add62bab57c3</cites><orcidid>0000-0002-9691-5111 ; 0000-0002-4854-9698 ; 0000-0002-3040-583X ; 0009-0003-9476-5783 ; 0000-0002-0598-3232 ; 0000-0003-2197-2610</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/PMC11226038/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226038/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38968295$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kenney, H Mark</creatorcontrib><creatorcontrib>Chen, Kiana L</creatorcontrib><creatorcontrib>Schnur, Lindsay</creatorcontrib><creatorcontrib>Fox, Jeffrey I</creatorcontrib><creatorcontrib>Wood, Ronald W</creatorcontrib><creatorcontrib>Xing, Lianping</creatorcontrib><creatorcontrib>Ritchlin, Christopher T</creatorcontrib><creatorcontrib>Rahimi, Homaira</creatorcontrib><creatorcontrib>Schwarz, Edward M</creatorcontrib><creatorcontrib>Awad, Hani A</creatorcontrib><title>High-throughput micro-CT analysis identifies sex-dependent biomarkers of erosive arthritis in TNF-Tg mice and differential response to anti-TNF therapy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Development of reliable disease activity biomarkers is critical for diagnostics, prognostics, and novel drug development. Although computed tomography (CT) is the gold-standard for quantification of bone erosions, there are no consensus approaches or rationales for utilization of specific outcome measures of erosive arthritis in complex joints. In the case of preclinical models, such as sexually dimorphic tumor necrosis factor transgenic (TNF-Tg) mice, disease severity is routinely quantified in the ankle through manual segmentation of the talus or small regions of adjacent bones primarily due to the ease in measurement. Herein, we sought to determine the particular hindpaw bones that represent reliable biomarkers of sex-dependent disease progression to guide future investigation and analysis.
Hindpaw micro-CT was performed on wild-type (n = 4 male, n = 4 female) and TNF-Tg (n = 4 male, n = 7 female) mice at monthly intervals from 2-5 (females) and 2-8-months (males) of age, since female TNF-Tg mice exhibit early mortality from cardiopulmonary disease at approximately 5-6-months. Further, 8-month-old WT (n = 4) and TNF-Tg males treated with anti-TNF monoclonal antibodies (n = 5) or IgG placebo isotype controls (n = 6) for 6-weeks were imaged with micro-CT every 3-weeks. For image analysis, we utilized our recently developed high-throughput and semi-automated segmentation strategy in Amira software. Synovial and osteoclast histology of ankle joints was quantified using Visiopharm.
First, we demonstrated that the accuracy of automated segmentation, determined through analysis of ~9000 individual bones by a single user, was comparable in wild-type and TNF-Tg hindpaws before correction (79.2±8.9% vs 80.1±5.1%, p = 0.52). Compared to other bone compartments, the tarsal region demonstrated a sudden, specific, and significant bone volume reduction in female TNF-Tg mice, but not in males, by 5-months (4-months 4.3± 0.22 vs 5-months 3.4± 0.62 mm3, p<0.05). Specifically, the cuboid showed significantly reduced bone volumes at early timepoints compared to other tarsals (i.e., 4-months: Cuboid -24.1±7.2% vs Talus -9.0±5.9% of 2-month baseline). Additional bones localized to the anterolateral region of the ankle also exhibited dramatic erosions in the tarsal region of females, coinciding with increased synovitis and osteoclasts. In TNF-Tg male mice with severe arthritis, the talus and calcaneus exhibited the most sensitive response to anti-TNF therapy measured by effect size of bone volume change over treatment period.
We demonstrated that sexually dimorphic changes in arthritic hindpaws of TNF-Tg mice are bone-specific, where the cuboid serves as a reliable early biomarker of erosive arthritis in female mice. Adoption of automated segmentation approaches in pre-clinical or clinical models has potential to translate quantitative biomarkers to monitor bone erosions in disease and evaluate therapeutic efficacy.</description><subject>Animal models</subject><subject>Animals</subject><subject>Ankle</subject><subject>Arthritis</subject><subject>Biological markers</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Bone density</subject><subject>Bones</subject><subject>Calcaneus</subject><subject>Computed tomography</subject><subject>CT imaging</subject><subject>Disease Models, Animal</subject><subject>Diseases</subject><subject>Drug development</subject><subject>Effectiveness</subject><subject>Engineering and Technology</subject><subject>Female</subject><subject>Females</subject><subject>Genetic engineering</subject><subject>Health aspects</subject><subject>Histology</subject><subject>Image analysis</subject><subject>Image 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micro-CT analysis identifies sex-dependent biomarkers of erosive arthritis in TNF-Tg mice and differential response to anti-TNF therapy</title><author>Kenney, H Mark ; Chen, Kiana L ; Schnur, Lindsay ; Fox, Jeffrey I ; Wood, Ronald W ; Xing, Lianping ; Ritchlin, Christopher T ; Rahimi, Homaira ; Schwarz, Edward M ; Awad, Hani A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c642t-d1f6463e685a9bfce9d35d521b1a6625f963ce488e20c85c4aea9add62bab57c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Ankle</topic><topic>Arthritis</topic><topic>Biological markers</topic><topic>Biology and Life Sciences</topic><topic>Biomarkers</topic><topic>Bone density</topic><topic>Bones</topic><topic>Calcaneus</topic><topic>Computed tomography</topic><topic>CT imaging</topic><topic>Disease Models, 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Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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>Kenney, H Mark</au><au>Chen, Kiana L</au><au>Schnur, Lindsay</au><au>Fox, Jeffrey I</au><au>Wood, Ronald W</au><au>Xing, Lianping</au><au>Ritchlin, Christopher T</au><au>Rahimi, Homaira</au><au>Schwarz, Edward M</au><au>Awad, Hani A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High-throughput micro-CT analysis identifies sex-dependent biomarkers of erosive arthritis in TNF-Tg mice and differential response to anti-TNF therapy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2024-07-05</date><risdate>2024</risdate><volume>19</volume><issue>7</issue><spage>e0305623</spage><pages>e0305623-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Development of reliable disease activity biomarkers is critical for diagnostics, prognostics, and novel drug development. Although computed tomography (CT) is the gold-standard for quantification of bone erosions, there are no consensus approaches or rationales for utilization of specific outcome measures of erosive arthritis in complex joints. In the case of preclinical models, such as sexually dimorphic tumor necrosis factor transgenic (TNF-Tg) mice, disease severity is routinely quantified in the ankle through manual segmentation of the talus or small regions of adjacent bones primarily due to the ease in measurement. Herein, we sought to determine the particular hindpaw bones that represent reliable biomarkers of sex-dependent disease progression to guide future investigation and analysis.
Hindpaw micro-CT was performed on wild-type (n = 4 male, n = 4 female) and TNF-Tg (n = 4 male, n = 7 female) mice at monthly intervals from 2-5 (females) and 2-8-months (males) of age, since female TNF-Tg mice exhibit early mortality from cardiopulmonary disease at approximately 5-6-months. Further, 8-month-old WT (n = 4) and TNF-Tg males treated with anti-TNF monoclonal antibodies (n = 5) or IgG placebo isotype controls (n = 6) for 6-weeks were imaged with micro-CT every 3-weeks. For image analysis, we utilized our recently developed high-throughput and semi-automated segmentation strategy in Amira software. Synovial and osteoclast histology of ankle joints was quantified using Visiopharm.
First, we demonstrated that the accuracy of automated segmentation, determined through analysis of ~9000 individual bones by a single user, was comparable in wild-type and TNF-Tg hindpaws before correction (79.2±8.9% vs 80.1±5.1%, p = 0.52). Compared to other bone compartments, the tarsal region demonstrated a sudden, specific, and significant bone volume reduction in female TNF-Tg mice, but not in males, by 5-months (4-months 4.3± 0.22 vs 5-months 3.4± 0.62 mm3, p<0.05). Specifically, the cuboid showed significantly reduced bone volumes at early timepoints compared to other tarsals (i.e., 4-months: Cuboid -24.1±7.2% vs Talus -9.0±5.9% of 2-month baseline). Additional bones localized to the anterolateral region of the ankle also exhibited dramatic erosions in the tarsal region of females, coinciding with increased synovitis and osteoclasts. In TNF-Tg male mice with severe arthritis, the talus and calcaneus exhibited the most sensitive response to anti-TNF therapy measured by effect size of bone volume change over treatment period.
We demonstrated that sexually dimorphic changes in arthritic hindpaws of TNF-Tg mice are bone-specific, where the cuboid serves as a reliable early biomarker of erosive arthritis in female mice. Adoption of automated segmentation approaches in pre-clinical or clinical models has potential to translate quantitative biomarkers to monitor bone erosions in disease and evaluate therapeutic efficacy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>38968295</pmid><doi>10.1371/journal.pone.0305623</doi><tpages>e0305623</tpages><orcidid>https://orcid.org/0000-0002-9691-5111</orcidid><orcidid>https://orcid.org/0000-0002-4854-9698</orcidid><orcidid>https://orcid.org/0000-0002-3040-583X</orcidid><orcidid>https://orcid.org/0009-0003-9476-5783</orcidid><orcidid>https://orcid.org/0000-0002-0598-3232</orcidid><orcidid>https://orcid.org/0000-0003-2197-2610</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2024-07, Vol.19 (7), p.e0305623 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_3076243474 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animal models Animals Ankle Arthritis Biological markers Biology and Life Sciences Biomarkers Bone density Bones Calcaneus Computed tomography CT imaging Disease Models, Animal Diseases Drug development Effectiveness Engineering and Technology Female Females Genetic engineering Health aspects Histology Image analysis Image processing Immunoglobulin G Inflammation Joint diseases Joints (anatomy) Magnetic resonance imaging Male Males Medicine and Health Sciences Mice Mice, Inbred C57BL Mice, Transgenic Monoclonal antibodies Osteoclasts Pathogenesis Research and Analysis Methods Segmentation Sex Characteristics Sex Factors Sexual dimorphism Soil erosion Synovitis Talus Transgenic mice Tumor necrosis factor Tumor Necrosis Factor-alpha - antagonists & inhibitors X-Ray Microtomography - methods |
| title | High-throughput micro-CT analysis identifies sex-dependent biomarkers of erosive arthritis in TNF-Tg mice and differential response to anti-TNF therapy |
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