MicroRNA‐602 and MicroRNA‐608 Regulate Sonic Hedgehog Expression via Target Sites in the Coding Region in Human Chondrocytes
Objective Hedgehog (HH) signaling has recently been associated with cartilage degradation in osteoarthritis (OA). Because interleukin‐1β (IL‐1β) has been implicated as a principal instigator of OA, we sought to determine whether IL‐1β induces the expression of sonic HH (SHH) and its regulation by mi...
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| Veröffentlicht in: | Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2015-02, Vol.67 (2), p.423-434 |
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| creator | Akhtar, Nahid Makki, Mohammad S. Haqqi, Tariq M. |
| description | Objective
Hedgehog (HH) signaling has recently been associated with cartilage degradation in osteoarthritis (OA). Because interleukin‐1β (IL‐1β) has been implicated as a principal instigator of OA, we sought to determine whether IL‐1β induces the expression of sonic HH (SHH) and its regulation by microRNAs (miRNAs) in human chondrocytes.
Methods
Expression of SHH protein in human OA cartilage and in an animal model of OA was determined by immunohistochemical analysis and immunofluorescence analysis, respectively. Gene and protein expression in IL‐1β– or SHH‐stimulated OA chondrocytes was determined by TaqMan assays and Western blotting, respectively. The effect of overexpression of miRNA‐602 (miR‐602) and miR‐608 or their antagomirs on SHH expression was evaluated by transient transfection of human chondrocytes and HEK 293 cells. The role of signaling pathways was evaluated using small molecule inhibitors. Binding of miRNAs with the putative seed sequence in SHH messenger RNA (mRNA) was validated using a luciferase reporter assay.
Results
Expression of SHH, patched 1, Gli‐1, HH‐interacting protein, matrix metalloproteinase 13 (MMP‐13), and Colα1(X) was high in damaged OA cartilage. In damaged cartilage and in IL‐1β–stimulated OA chondrocytes, expression of SHH was inversely correlated with expression of miR‐608. Cotransfection of OA chondrocytes with miR‐608 or miR‐602 mimic inhibited reporter activity, and mutation of the miRNA seed sequences abolished the repression of reporter activity. Overexpression of miR‐602 or miR‐608 inhibited the expression of SHH mRNA and protein, and this was abrogated by antagomirs. Stimulation with recombinant human SHH protein up‐regulated MMP‐13 expression, and inhibition of HH signaling blocked MMP‐13 expression in OA chondrocytes.
Conclusion
MiR‐602 and miR‐608 are important posttranscription regulators of SHH expression in OA chondrocytes, and their suppression by IL‐1β may contribute to the enhanced expression of SHH and MMP‐13 in OA. |
| doi_str_mv | 10.1002/art.38952 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4539020</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3571032701</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4762-e813ec3e4439a9371425bbed9a87720564e7ee00c3d5bcb9760eacc74333813a3</originalsourceid><addsrcrecordid>eNqFks1OGzEQgK2qVUGUQ1-gstRLOQT8u7u-IEURbZCgSCE9W17vsDHa2MHepc2NR-gz9klwCKCCVNUXW-PPn2fsQegjJYeUEHZkYn_IKyXZG7TLOCtGkhH59mlNFd1B-yldkzxUSQoi36MdJnklhWC76O7c2Rhm38d_7n4XhGHjG_wiVOEZtENnesCXwTuLp9C0sAgtPvm1ipCSCx7fOoPnJrbQ40vXQ8LO434BeBIa59uNYUPl4HRYGo8ni-CbGOw6ox_QuyvTJdh_nPfQj68n88l0dHbx7XQyPhtZURZsBBXlYDkIwZVRvKSCybqGRpmqLHPBhYASgBDLG1nbWpUFAWNtKTjn-ajhe-h4610N9RIaC76PptOr6JYmrnUwTr_c8W6h23CrheSKMJIFXx4FMdwMkHq9dMlC1xkPYUiaFgURTMl84f9RyXL-imysn1-h12GIPr9EpkQllawozdTBlsofk1KEq-e8KdGbLtC5C_RDF2T209-FPpNPf56Boy3w03Ww_rdJj2fzrfIey8W8KA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1648595811</pqid></control><display><type>article</type><title>MicroRNA‐602 and MicroRNA‐608 Regulate Sonic Hedgehog Expression via Target Sites in the Coding Region in Human Chondrocytes</title><source>MEDLINE</source><source>Wiley Online Library All Journals</source><source>Alma/SFX Local Collection</source><creator>Akhtar, Nahid ; Makki, Mohammad S. ; Haqqi, Tariq M.</creator><creatorcontrib>Akhtar, Nahid ; Makki, Mohammad S. ; Haqqi, Tariq M.</creatorcontrib><description>Objective
Hedgehog (HH) signaling has recently been associated with cartilage degradation in osteoarthritis (OA). Because interleukin‐1β (IL‐1β) has been implicated as a principal instigator of OA, we sought to determine whether IL‐1β induces the expression of sonic HH (SHH) and its regulation by microRNAs (miRNAs) in human chondrocytes.
Methods
Expression of SHH protein in human OA cartilage and in an animal model of OA was determined by immunohistochemical analysis and immunofluorescence analysis, respectively. Gene and protein expression in IL‐1β– or SHH‐stimulated OA chondrocytes was determined by TaqMan assays and Western blotting, respectively. The effect of overexpression of miRNA‐602 (miR‐602) and miR‐608 or their antagomirs on SHH expression was evaluated by transient transfection of human chondrocytes and HEK 293 cells. The role of signaling pathways was evaluated using small molecule inhibitors. Binding of miRNAs with the putative seed sequence in SHH messenger RNA (mRNA) was validated using a luciferase reporter assay.
Results
Expression of SHH, patched 1, Gli‐1, HH‐interacting protein, matrix metalloproteinase 13 (MMP‐13), and Colα1(X) was high in damaged OA cartilage. In damaged cartilage and in IL‐1β–stimulated OA chondrocytes, expression of SHH was inversely correlated with expression of miR‐608. Cotransfection of OA chondrocytes with miR‐608 or miR‐602 mimic inhibited reporter activity, and mutation of the miRNA seed sequences abolished the repression of reporter activity. Overexpression of miR‐602 or miR‐608 inhibited the expression of SHH mRNA and protein, and this was abrogated by antagomirs. Stimulation with recombinant human SHH protein up‐regulated MMP‐13 expression, and inhibition of HH signaling blocked MMP‐13 expression in OA chondrocytes.
Conclusion
MiR‐602 and miR‐608 are important posttranscription regulators of SHH expression in OA chondrocytes, and their suppression by IL‐1β may contribute to the enhanced expression of SHH and MMP‐13 in OA.</description><identifier>ISSN: 2326-5191</identifier><identifier>EISSN: 2326-5205</identifier><identifier>DOI: 10.1002/art.38952</identifier><identifier>PMID: 25385442</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Aged ; Animals ; Anterior Cruciate Ligament - surgery ; Cells, Cultured ; Chondrocytes - drug effects ; Chondrocytes - metabolism ; Chondrocytes - pathology ; Disease Models, Animal ; Female ; Gene Expression Regulation - genetics ; Gene Expression Regulation - physiology ; Hedgehog Proteins - genetics ; Hedgehog Proteins - metabolism ; HEK293 Cells ; Humans ; In Vitro Techniques ; Interleukin-1beta - pharmacology ; Kinases ; Male ; Matrix Metalloproteinase 13 - metabolism ; Medical research ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Middle Aged ; Open Reading Frames - genetics ; Open Reading Frames - physiology ; Osteoarthritis, Knee - etiology ; Osteoarthritis, Knee - metabolism ; Osteoarthritis, Knee - pathology ; Proteins ; Rabbits ; Signal Transduction - genetics ; Signal Transduction - physiology ; Transfection ; Up-Regulation - drug effects ; Up-Regulation - genetics ; Up-Regulation - physiology</subject><ispartof>Arthritis & rheumatology (Hoboken, N.J.), 2015-02, Vol.67 (2), p.423-434</ispartof><rights>Copyright © 2015 by the American College of Rheumatology</rights><rights>Copyright © 2015 by the American College of Rheumatology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4762-e813ec3e4439a9371425bbed9a87720564e7ee00c3d5bcb9760eacc74333813a3</citedby><cites>FETCH-LOGICAL-c4762-e813ec3e4439a9371425bbed9a87720564e7ee00c3d5bcb9760eacc74333813a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fart.38952$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fart.38952$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25385442$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akhtar, Nahid</creatorcontrib><creatorcontrib>Makki, Mohammad S.</creatorcontrib><creatorcontrib>Haqqi, Tariq M.</creatorcontrib><title>MicroRNA‐602 and MicroRNA‐608 Regulate Sonic Hedgehog Expression via Target Sites in the Coding Region in Human Chondrocytes</title><title>Arthritis & rheumatology (Hoboken, N.J.)</title><addtitle>Arthritis Rheumatol</addtitle><description>Objective
Hedgehog (HH) signaling has recently been associated with cartilage degradation in osteoarthritis (OA). Because interleukin‐1β (IL‐1β) has been implicated as a principal instigator of OA, we sought to determine whether IL‐1β induces the expression of sonic HH (SHH) and its regulation by microRNAs (miRNAs) in human chondrocytes.
Methods
Expression of SHH protein in human OA cartilage and in an animal model of OA was determined by immunohistochemical analysis and immunofluorescence analysis, respectively. Gene and protein expression in IL‐1β– or SHH‐stimulated OA chondrocytes was determined by TaqMan assays and Western blotting, respectively. The effect of overexpression of miRNA‐602 (miR‐602) and miR‐608 or their antagomirs on SHH expression was evaluated by transient transfection of human chondrocytes and HEK 293 cells. The role of signaling pathways was evaluated using small molecule inhibitors. Binding of miRNAs with the putative seed sequence in SHH messenger RNA (mRNA) was validated using a luciferase reporter assay.
Results
Expression of SHH, patched 1, Gli‐1, HH‐interacting protein, matrix metalloproteinase 13 (MMP‐13), and Colα1(X) was high in damaged OA cartilage. In damaged cartilage and in IL‐1β–stimulated OA chondrocytes, expression of SHH was inversely correlated with expression of miR‐608. Cotransfection of OA chondrocytes with miR‐608 or miR‐602 mimic inhibited reporter activity, and mutation of the miRNA seed sequences abolished the repression of reporter activity. Overexpression of miR‐602 or miR‐608 inhibited the expression of SHH mRNA and protein, and this was abrogated by antagomirs. Stimulation with recombinant human SHH protein up‐regulated MMP‐13 expression, and inhibition of HH signaling blocked MMP‐13 expression in OA chondrocytes.
Conclusion
MiR‐602 and miR‐608 are important posttranscription regulators of SHH expression in OA chondrocytes, and their suppression by IL‐1β may contribute to the enhanced expression of SHH and MMP‐13 in OA.</description><subject>Aged</subject><subject>Animals</subject><subject>Anterior Cruciate Ligament - surgery</subject><subject>Cells, Cultured</subject><subject>Chondrocytes - drug effects</subject><subject>Chondrocytes - metabolism</subject><subject>Chondrocytes - pathology</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gene Expression Regulation - genetics</subject><subject>Gene Expression Regulation - physiology</subject><subject>Hedgehog Proteins - genetics</subject><subject>Hedgehog Proteins - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Interleukin-1beta - pharmacology</subject><subject>Kinases</subject><subject>Male</subject><subject>Matrix Metalloproteinase 13 - metabolism</subject><subject>Medical research</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>Middle Aged</subject><subject>Open Reading Frames - genetics</subject><subject>Open Reading Frames - physiology</subject><subject>Osteoarthritis, Knee - etiology</subject><subject>Osteoarthritis, Knee - metabolism</subject><subject>Osteoarthritis, Knee - pathology</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Signal Transduction - genetics</subject><subject>Signal Transduction - physiology</subject><subject>Transfection</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - genetics</subject><subject>Up-Regulation - physiology</subject><issn>2326-5191</issn><issn>2326-5205</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks1OGzEQgK2qVUGUQ1-gstRLOQT8u7u-IEURbZCgSCE9W17vsDHa2MHepc2NR-gz9klwCKCCVNUXW-PPn2fsQegjJYeUEHZkYn_IKyXZG7TLOCtGkhH59mlNFd1B-yldkzxUSQoi36MdJnklhWC76O7c2Rhm38d_7n4XhGHjG_wiVOEZtENnesCXwTuLp9C0sAgtPvm1ipCSCx7fOoPnJrbQ40vXQ8LO434BeBIa59uNYUPl4HRYGo8ni-CbGOw6ox_QuyvTJdh_nPfQj68n88l0dHbx7XQyPhtZURZsBBXlYDkIwZVRvKSCybqGRpmqLHPBhYASgBDLG1nbWpUFAWNtKTjn-ajhe-h4610N9RIaC76PptOr6JYmrnUwTr_c8W6h23CrheSKMJIFXx4FMdwMkHq9dMlC1xkPYUiaFgURTMl84f9RyXL-imysn1-h12GIPr9EpkQllawozdTBlsofk1KEq-e8KdGbLtC5C_RDF2T209-FPpNPf56Boy3w03Ww_rdJj2fzrfIey8W8KA</recordid><startdate>201502</startdate><enddate>201502</enddate><creator>Akhtar, Nahid</creator><creator>Makki, Mohammad S.</creator><creator>Haqqi, Tariq M.</creator><general>Wiley Subscription Services, Inc</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>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201502</creationdate><title>MicroRNA‐602 and MicroRNA‐608 Regulate Sonic Hedgehog Expression via Target Sites in the Coding Region in Human Chondrocytes</title><author>Akhtar, Nahid ; Makki, Mohammad S. ; Haqqi, Tariq M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4762-e813ec3e4439a9371425bbed9a87720564e7ee00c3d5bcb9760eacc74333813a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>Animals</topic><topic>Anterior Cruciate Ligament - surgery</topic><topic>Cells, Cultured</topic><topic>Chondrocytes - drug effects</topic><topic>Chondrocytes - metabolism</topic><topic>Chondrocytes - pathology</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Gene Expression Regulation - genetics</topic><topic>Gene Expression Regulation - physiology</topic><topic>Hedgehog Proteins - genetics</topic><topic>Hedgehog Proteins - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Interleukin-1beta - pharmacology</topic><topic>Kinases</topic><topic>Male</topic><topic>Matrix Metalloproteinase 13 - metabolism</topic><topic>Medical research</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>Middle Aged</topic><topic>Open Reading Frames - genetics</topic><topic>Open Reading Frames - physiology</topic><topic>Osteoarthritis, Knee - etiology</topic><topic>Osteoarthritis, Knee - metabolism</topic><topic>Osteoarthritis, Knee - pathology</topic><topic>Proteins</topic><topic>Rabbits</topic><topic>Signal Transduction - genetics</topic><topic>Signal Transduction - physiology</topic><topic>Transfection</topic><topic>Up-Regulation - drug effects</topic><topic>Up-Regulation - genetics</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Akhtar, Nahid</creatorcontrib><creatorcontrib>Makki, Mohammad S.</creatorcontrib><creatorcontrib>Haqqi, Tariq M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akhtar, Nahid</au><au>Makki, Mohammad S.</au><au>Haqqi, Tariq M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MicroRNA‐602 and MicroRNA‐608 Regulate Sonic Hedgehog Expression via Target Sites in the Coding Region in Human Chondrocytes</atitle><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle><addtitle>Arthritis Rheumatol</addtitle><date>2015-02</date><risdate>2015</risdate><volume>67</volume><issue>2</issue><spage>423</spage><epage>434</epage><pages>423-434</pages><issn>2326-5191</issn><eissn>2326-5205</eissn><abstract>Objective
Hedgehog (HH) signaling has recently been associated with cartilage degradation in osteoarthritis (OA). Because interleukin‐1β (IL‐1β) has been implicated as a principal instigator of OA, we sought to determine whether IL‐1β induces the expression of sonic HH (SHH) and its regulation by microRNAs (miRNAs) in human chondrocytes.
Methods
Expression of SHH protein in human OA cartilage and in an animal model of OA was determined by immunohistochemical analysis and immunofluorescence analysis, respectively. Gene and protein expression in IL‐1β– or SHH‐stimulated OA chondrocytes was determined by TaqMan assays and Western blotting, respectively. The effect of overexpression of miRNA‐602 (miR‐602) and miR‐608 or their antagomirs on SHH expression was evaluated by transient transfection of human chondrocytes and HEK 293 cells. The role of signaling pathways was evaluated using small molecule inhibitors. Binding of miRNAs with the putative seed sequence in SHH messenger RNA (mRNA) was validated using a luciferase reporter assay.
Results
Expression of SHH, patched 1, Gli‐1, HH‐interacting protein, matrix metalloproteinase 13 (MMP‐13), and Colα1(X) was high in damaged OA cartilage. In damaged cartilage and in IL‐1β–stimulated OA chondrocytes, expression of SHH was inversely correlated with expression of miR‐608. Cotransfection of OA chondrocytes with miR‐608 or miR‐602 mimic inhibited reporter activity, and mutation of the miRNA seed sequences abolished the repression of reporter activity. Overexpression of miR‐602 or miR‐608 inhibited the expression of SHH mRNA and protein, and this was abrogated by antagomirs. Stimulation with recombinant human SHH protein up‐regulated MMP‐13 expression, and inhibition of HH signaling blocked MMP‐13 expression in OA chondrocytes.
Conclusion
MiR‐602 and miR‐608 are important posttranscription regulators of SHH expression in OA chondrocytes, and their suppression by IL‐1β may contribute to the enhanced expression of SHH and MMP‐13 in OA.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>25385442</pmid><doi>10.1002/art.38952</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Animals Anterior Cruciate Ligament - surgery Cells, Cultured Chondrocytes - drug effects Chondrocytes - metabolism Chondrocytes - pathology Disease Models, Animal Female Gene Expression Regulation - genetics Gene Expression Regulation - physiology Hedgehog Proteins - genetics Hedgehog Proteins - metabolism HEK293 Cells Humans In Vitro Techniques Interleukin-1beta - pharmacology Kinases Male Matrix Metalloproteinase 13 - metabolism Medical research MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Middle Aged Open Reading Frames - genetics Open Reading Frames - physiology Osteoarthritis, Knee - etiology Osteoarthritis, Knee - metabolism Osteoarthritis, Knee - pathology Proteins Rabbits Signal Transduction - genetics Signal Transduction - physiology Transfection Up-Regulation - drug effects Up-Regulation - genetics Up-Regulation - physiology |
| title | MicroRNA‐602 and MicroRNA‐608 Regulate Sonic Hedgehog Expression via Target Sites in the Coding Region in Human Chondrocytes |
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