{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:18:24Z","timestamp":1787170704169,"version":"build-2736575974"},"reference-count":39,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T00:00:00Z","timestamp":1708041600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Kaohsiung J of Med Scie"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and the role of HOXA transcript at the distal tip (HOTTIP) in its pathogenesis remains underexplored. This study investigates the mechanism by which HOTTIP influences apoptosis and the inflammatory response of fibroblast\u2010like synoviocytes (FLS). An RA mouse model was established, and clinical scores were analyzed. Pathological changes in synovial tissues, bone mineral density (BMD) of the paws, serum tartrate\u2010resistant acid phosphatase (TRAP) activity, and TNF\u2010\u03b1 and IL\u20101\u03b2 levels were assessed. FLS were transfected, and cell proliferation and apoptosis were examined. The RNA\u2010pull\u2010down assay determined HOTTIP's interaction with mixed\u2010lineage leukemia 1 (MLL1), while RNA immunoprecipitation assay measured HOTTIP expression pulled down by MLL1. The levels of MLL1 and toll\u2010like receptor 4 (TLR4) after MLL1 overexpression based on HOTTIP silencing were determined. Chromatin immunoprecipitation (ChIP) was performed with H3K4me3 as an antibody, followed by the evaluation of TLR4 expression. HOTTIP expression was elevated in RA mouse synovial tissues. Inhibition of HOTTIP led to reduced clinical scores, inflammatory infiltration, synovial hyperplasia, TRAP activity, and TNF\u2010\u03b1 and IL\u20101\u03b2 levels, along with increased BMD. In vitro Interference with HOTTIP suppressed RA\u2010FLS apoptosis and inflammation. HOTTIP upregulated TLR4 expression by recruiting MLL1 to facilitate TLR4 promoter methylation. MLL1 overexpression reversed HOTTIP silencing\u2010mediated repression of RA\u2010FLS apoptosis. Activation of H3K4 methylation counteracted HOTTIP knockout, ameliorating the inflammatory response. HOTTIP regulates TLR4 expression by recruiting MLL1, leading to TLR4 promoter methylation, thereby suppressing RA\u2010FLS proliferation and inducing cell apoptosis and inflammatory response in RA.<\/jats:p>","DOI":"10.1002\/kjm2.12805","type":"journal-article","created":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T08:39:50Z","timestamp":1708072790000},"page":"335-347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp>LncRNA HOTTIP<\/scp>\n                    regulates\n                    <scp>TLR4<\/scp>\n                    promoter methylation by recruiting\n                    <scp>H3K4<\/scp>\n                    methyltransferase\n                    <scp>MLL1<\/scp>\n                    to affect apoptosis and inflammatory response of fibroblast\u2010like synoviocyte in rheumatoid arthritis"],"prefix":"10.1002","volume":"40","author":[{"given":"Guan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics The Affiliated Hospital of Southwest Medical University, Sichuan Provincial Laboratory of Orthopaedic Engineering Luzhou  Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Lin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Affiliated Hospital of Southwest Medical University, Sichuan Provincial Laboratory of Orthopaedic Engineering Luzhou  Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi\u2010Hai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Affiliated Hospital of Southwest Medical University, Sichuan Provincial Laboratory of Orthopaedic Engineering Luzhou  Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Affiliated Hospital of Southwest Medical University, Sichuan Provincial Laboratory of Orthopaedic Engineering Luzhou  Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8053-4030","authenticated-orcid":false,"given":"Yao","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center Southwest Medical University  Luzhou Sichuan 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