Proteolysis and cartilage development are activated in the synovium after surgical induction of post traumatic osteoarthritis
Anterior cruciate ligament (ACL) transection surgery in the minipig induces post-traumatic osteoarthritis (PTOA) in a pattern similar to that seen in human patients after ACL injury. Prior studies have reported the presence of cartilage matrix-degrading proteases, such as Matrix metalloproteinase-1...
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| creator | Ayturk, Ugur M Sieker, Jakob T Haslauer, Carla M Proffen, Benedikt L Weissenberger, Manuela H Warman, Matthew L Fleming, Braden C Murray, Martha M |
| description | Anterior cruciate ligament (ACL) transection surgery in the minipig induces post-traumatic osteoarthritis (PTOA) in a pattern similar to that seen in human patients after ACL injury. Prior studies have reported the presence of cartilage matrix-degrading proteases, such as Matrix metalloproteinase-1 (MMP-1) and A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), in the synovial fluid of injured or arthritic joints; however, the tissue origin of these proteases is unknown. The objective of this study was to identify transcriptional processes activated in the synovium after surgical induction of PTOA with ACL transection, and to determine if processes associated with proteolysis were enriched in the synovium after ACL transection. Unilateral ACL transection was performed in adolescent Yucatan minipigs and synovium samples were collected at 1, 5, 9, and 14 days post-injury. Transcriptome-wide gene expression levels were determined using bulk RNA-Sequencing in the surgical animals and control animals with healthy knees. The greatest number of transcripts with significant changes was observed 1 day after injury. These changes were primarily associated with cellular proliferation, consistent with measurements of increased cellularity of the synovium at the two-week time point. At five to 14 days, the expression of transcripts relating to proteolysis and cartilage development was significantly enriched. While protease inhibitor-encoding transcripts (TIMP2, TIMP3) represented the largest fraction of protease-associated transcripts in the uninjured synovium, protease-encoding transcripts (including MMP1, MMP2, ADAMTS4) predominated after surgery. Cartilage development-associated transcripts that are typically not expressed by synovial cells, such as ACAN and COMP, were enriched in the synovium following ACL-transection. The upregulation in both catabolic processes (proteolysis) and anabolic processes (cartilage development) suggests that the synovium plays a complex, balancing role in the early response to PTOA induction. |
| doi_str_mv | 10.1371/journal.pone.0229449 |
| format | Article |
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Prior studies have reported the presence of cartilage matrix-degrading proteases, such as Matrix metalloproteinase-1 (MMP-1) and A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), in the synovial fluid of injured or arthritic joints; however, the tissue origin of these proteases is unknown. The objective of this study was to identify transcriptional processes activated in the synovium after surgical induction of PTOA with ACL transection, and to determine if processes associated with proteolysis were enriched in the synovium after ACL transection. Unilateral ACL transection was performed in adolescent Yucatan minipigs and synovium samples were collected at 1, 5, 9, and 14 days post-injury. Transcriptome-wide gene expression levels were determined using bulk RNA-Sequencing in the surgical animals and control animals with healthy knees. The greatest number of transcripts with significant changes was observed 1 day after injury. These changes were primarily associated with cellular proliferation, consistent with measurements of increased cellularity of the synovium at the two-week time point. At five to 14 days, the expression of transcripts relating to proteolysis and cartilage development was significantly enriched. While protease inhibitor-encoding transcripts (TIMP2, TIMP3) represented the largest fraction of protease-associated transcripts in the uninjured synovium, protease-encoding transcripts (including MMP1, MMP2, ADAMTS4) predominated after surgery. Cartilage development-associated transcripts that are typically not expressed by synovial cells, such as ACAN and COMP, were enriched in the synovium following ACL-transection. The upregulation in both catabolic processes (proteolysis) and anabolic processes (cartilage development) suggests that the synovium plays a complex, balancing role in the early response to PTOA induction.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0229449</identifier><identifier>PMID: 32107493</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ADAM protein ; Analgesics ; Animals ; Anterior cruciate ligament ; Arthritis ; Biology and Life Sciences ; Biomarkers - metabolism ; Biomedical materials ; Cartilage ; Cartilage diseases ; Cartilage, Articular - metabolism ; Cartilage, Articular - pathology ; Chondrogenesis - genetics ; Collagen ; Cytokines ; Enrichment ; Euthanasia ; Extracellular matrix ; Gelatinase A ; Gene expression ; Gene sequencing ; Genes ; Hospitals ; Injuries ; Interstitial collagenase ; Joint and ligament injuries ; Knee ; Ligaments ; Male ; Matrix metalloproteinase ; Matrix metalloproteinases ; Medical research ; Medical schools ; Medicine and Health Sciences ; Osteoarthritis ; Osteoarthritis - genetics ; Osteoarthritis - pathology ; Osteoarthritis - surgery ; Protease ; Protease inhibitors ; Proteases ; Proteinase inhibitors ; Proteolysis ; Ribonucleic acid ; RNA ; Sports injuries ; Surgery ; Swine ; Swine, Miniature ; Synovial fluid ; Synovial Membrane - metabolism ; Synovial Membrane - pathology ; Synovium ; Thrombospondin ; Time ; Tissue inhibitor of metalloproteinase 2 ; Tissue inhibitor of metalloproteinase 3 ; Transcription ; Transcriptome</subject><ispartof>PloS one, 2020-02, Vol.15 (2), p.e0229449-e0229449</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Ayturk 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>2020 Ayturk et al 2020 Ayturk et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-cb3562c6dbb6cb77a47b2ca4638184fde64e2d8991bd781c7839ccc9a42bea1c3</citedby><cites>FETCH-LOGICAL-c692t-cb3562c6dbb6cb77a47b2ca4638184fde64e2d8991bd781c7839ccc9a42bea1c3</cites><orcidid>0000-0002-7841-425X ; 0000-0001-5086-9511</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/PMC7046188/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046188/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32107493$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>van Wijnen, Andre</contributor><creatorcontrib>Ayturk, Ugur M</creatorcontrib><creatorcontrib>Sieker, Jakob T</creatorcontrib><creatorcontrib>Haslauer, Carla M</creatorcontrib><creatorcontrib>Proffen, Benedikt L</creatorcontrib><creatorcontrib>Weissenberger, Manuela H</creatorcontrib><creatorcontrib>Warman, Matthew L</creatorcontrib><creatorcontrib>Fleming, Braden C</creatorcontrib><creatorcontrib>Murray, Martha M</creatorcontrib><title>Proteolysis and cartilage development are activated in the synovium after surgical induction of post traumatic osteoarthritis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Anterior cruciate ligament (ACL) transection surgery in the minipig induces post-traumatic osteoarthritis (PTOA) in a pattern similar to that seen in human patients after ACL injury. Prior studies have reported the presence of cartilage matrix-degrading proteases, such as Matrix metalloproteinase-1 (MMP-1) and A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), in the synovial fluid of injured or arthritic joints; however, the tissue origin of these proteases is unknown. The objective of this study was to identify transcriptional processes activated in the synovium after surgical induction of PTOA with ACL transection, and to determine if processes associated with proteolysis were enriched in the synovium after ACL transection. Unilateral ACL transection was performed in adolescent Yucatan minipigs and synovium samples were collected at 1, 5, 9, and 14 days post-injury. Transcriptome-wide gene expression levels were determined using bulk RNA-Sequencing in the surgical animals and control animals with healthy knees. The greatest number of transcripts with significant changes was observed 1 day after injury. These changes were primarily associated with cellular proliferation, consistent with measurements of increased cellularity of the synovium at the two-week time point. At five to 14 days, the expression of transcripts relating to proteolysis and cartilage development was significantly enriched. While protease inhibitor-encoding transcripts (TIMP2, TIMP3) represented the largest fraction of protease-associated transcripts in the uninjured synovium, protease-encoding transcripts (including MMP1, MMP2, ADAMTS4) predominated after surgery. Cartilage development-associated transcripts that are typically not expressed by synovial cells, such as ACAN and COMP, were enriched in the synovium following ACL-transection. 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genetics</subject><subject>Osteoarthritis - pathology</subject><subject>Osteoarthritis - surgery</subject><subject>Protease</subject><subject>Protease inhibitors</subject><subject>Proteases</subject><subject>Proteinase inhibitors</subject><subject>Proteolysis</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Sports injuries</subject><subject>Surgery</subject><subject>Swine</subject><subject>Swine, Miniature</subject><subject>Synovial fluid</subject><subject>Synovial Membrane - metabolism</subject><subject>Synovial Membrane - pathology</subject><subject>Synovium</subject><subject>Thrombospondin</subject><subject>Time</subject><subject>Tissue inhibitor of metalloproteinase 2</subject><subject>Tissue inhibitor of metalloproteinase 3</subject><subject>Transcription</subject><subject>Transcriptome</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</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>eNqNk12L1DAUhoso7rr6D0QDgujFjG2Spu2NsCx-DCys-HUbTtPTTpa0GZN0cC7872Z2ustU9kJyka_nvCd5k5Mkz7N0mbEie3dtRzeAWW7sgMuU0orz6kFymlWMLgRN2cOj8UnyxPvrNM1ZKcTj5ITRLC14xU6TP1-cDWjNzmtPYGiIAhe0gQ5Jg1s0dtPjEAg4JKCC3kLAhuiBhDUSvxvsVo89gTagI350nVZg4nYzRtYOxLZkY30gwcHYQ9CKxBnamGLtdND-afKoBePx2dSfJT8-fvh-8XlxefVpdXF-uVCiomGhapYLqkRT10LVRQG8qKkCLliZlbxtUHCkTVlVWd0UZaaKklVKqQo4rREyxc6SlwfdjbFeTs55SZkQImUlzyOxOhCNhWu5cboHt5MWtLxZsK6Te2OUQckVFKLmdczCeVmkkDNVly1rFYeWCoxa76dsY91jo6KBDsxMdL4z6LXs7FYWKRdZWUaBN5OAs79G9EH22is0Bga04825K55SVvCIvvoHvf92E9VBvIAeWhvzqr2oPBdZzlmelnut5T1UbA32WsVv1uq4Pgt4OwuITMDfoYPRe7n69vX_2aufc_b1EbtGMGHtrRn3f8rPQX4AlbPeO2zvTM5Sua-SWzfkvkrkVCUx7MXxA90F3ZYF-wtqGhBd</recordid><startdate>20200227</startdate><enddate>20200227</enddate><creator>Ayturk, Ugur M</creator><creator>Sieker, Jakob T</creator><creator>Haslauer, Carla M</creator><creator>Proffen, Benedikt L</creator><creator>Weissenberger, Manuela H</creator><creator>Warman, Matthew L</creator><creator>Fleming, Braden C</creator><creator>Murray, Martha M</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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-7841-425X</orcidid><orcidid>https://orcid.org/0000-0001-5086-9511</orcidid></search><sort><creationdate>20200227</creationdate><title>Proteolysis and cartilage development are activated in the synovium after surgical induction of post traumatic osteoarthritis</title><author>Ayturk, Ugur M ; Sieker, Jakob T ; Haslauer, Carla M ; Proffen, Benedikt L ; Weissenberger, Manuela H ; Warman, Matthew L ; Fleming, Braden C ; Murray, Martha M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-cb3562c6dbb6cb77a47b2ca4638184fde64e2d8991bd781c7839ccc9a42bea1c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>ADAM protein</topic><topic>Analgesics</topic><topic>Animals</topic><topic>Anterior cruciate ligament</topic><topic>Arthritis</topic><topic>Biology and Life Sciences</topic><topic>Biomarkers - 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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>Ayturk, Ugur M</au><au>Sieker, Jakob T</au><au>Haslauer, Carla M</au><au>Proffen, Benedikt L</au><au>Weissenberger, Manuela H</au><au>Warman, Matthew L</au><au>Fleming, Braden C</au><au>Murray, Martha M</au><au>van Wijnen, Andre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proteolysis and cartilage development are activated in the synovium after surgical induction of post traumatic osteoarthritis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-02-27</date><risdate>2020</risdate><volume>15</volume><issue>2</issue><spage>e0229449</spage><epage>e0229449</epage><pages>e0229449-e0229449</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Anterior cruciate ligament (ACL) transection surgery in the minipig induces post-traumatic osteoarthritis (PTOA) in a pattern similar to that seen in human patients after ACL injury. Prior studies have reported the presence of cartilage matrix-degrading proteases, such as Matrix metalloproteinase-1 (MMP-1) and A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), in the synovial fluid of injured or arthritic joints; however, the tissue origin of these proteases is unknown. The objective of this study was to identify transcriptional processes activated in the synovium after surgical induction of PTOA with ACL transection, and to determine if processes associated with proteolysis were enriched in the synovium after ACL transection. Unilateral ACL transection was performed in adolescent Yucatan minipigs and synovium samples were collected at 1, 5, 9, and 14 days post-injury. Transcriptome-wide gene expression levels were determined using bulk RNA-Sequencing in the surgical animals and control animals with healthy knees. The greatest number of transcripts with significant changes was observed 1 day after injury. These changes were primarily associated with cellular proliferation, consistent with measurements of increased cellularity of the synovium at the two-week time point. At five to 14 days, the expression of transcripts relating to proteolysis and cartilage development was significantly enriched. While protease inhibitor-encoding transcripts (TIMP2, TIMP3) represented the largest fraction of protease-associated transcripts in the uninjured synovium, protease-encoding transcripts (including MMP1, MMP2, ADAMTS4) predominated after surgery. Cartilage development-associated transcripts that are typically not expressed by synovial cells, such as ACAN and COMP, were enriched in the synovium following ACL-transection. The upregulation in both catabolic processes (proteolysis) and anabolic processes (cartilage development) suggests that the synovium plays a complex, balancing role in the early response to PTOA induction.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32107493</pmid><doi>10.1371/journal.pone.0229449</doi><tpages>e0229449</tpages><orcidid>https://orcid.org/0000-0002-7841-425X</orcidid><orcidid>https://orcid.org/0000-0001-5086-9511</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2020-02, Vol.15 (2), p.e0229449-e0229449 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2366603845 |
| 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 | ADAM protein Analgesics Animals Anterior cruciate ligament Arthritis Biology and Life Sciences Biomarkers - metabolism Biomedical materials Cartilage Cartilage diseases Cartilage, Articular - metabolism Cartilage, Articular - pathology Chondrogenesis - genetics Collagen Cytokines Enrichment Euthanasia Extracellular matrix Gelatinase A Gene expression Gene sequencing Genes Hospitals Injuries Interstitial collagenase Joint and ligament injuries Knee Ligaments Male Matrix metalloproteinase Matrix metalloproteinases Medical research Medical schools Medicine and Health Sciences Osteoarthritis Osteoarthritis - genetics Osteoarthritis - pathology Osteoarthritis - surgery Protease Protease inhibitors Proteases Proteinase inhibitors Proteolysis Ribonucleic acid RNA Sports injuries Surgery Swine Swine, Miniature Synovial fluid Synovial Membrane - metabolism Synovial Membrane - pathology Synovium Thrombospondin Time Tissue inhibitor of metalloproteinase 2 Tissue inhibitor of metalloproteinase 3 Transcription Transcriptome |
| title | Proteolysis and cartilage development are activated in the synovium after surgical induction of post traumatic osteoarthritis |
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