{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T20:00:19Z","timestamp":1773432019342,"version":"3.50.1"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Tissue inhibitor of metalloproteinase 3 (TIMP-3) is a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) and ADAM\/ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family enzymes that regulate extracellular matrix (ECM) homeostasis. Because these enzymes play key roles in articular cartilage turnover, TIMP-3\u2013mediated inhibition protects against cartilage degradation, a hallmark of osteoarthritis (OA), and has been explored as a therapeutic target. Nonetheless, unexpected detrimental effects of TIMP-3 on bone mass and structure have been reported in transgenic mice overexpressing TIMP-3 in cartilage. Mechanistically, TIMP-3 binds catabolic enzymes and blocks their active sites but also interacts with low-density lipoprotein receptor-related protein 1 (LRP-1) and sulfated proteoglycans in the ECM, processes that regulate its half-life through a balance between endocytosis and ECM retention and may influence cell signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated whether TIMP-3 affects gene expression in\n                      <jats:italic>ex vivo<\/jats:italic>\n                      mouse articular cartilage explants under normoxia or physiological hypoxia (3% O\n                      <jats:sub>2<\/jats:sub>\n                      ). Femoral head cartilage explants were treated with recombinant TIMP-3 and then processed for RNA sequencing (RNA-seq).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Hypoxia alone induced a strong transcriptional response, confirming the model\u2019s responsiveness, whereas TIMP-3 altered the expression of only a small subset of genes. RT-qPCR validation confirmed TIMP-3\u2013mediated upregulation of inflammation-associated genes, including\n                      <jats:italic>Saa3<\/jats:italic>\n                      under both oxygen conditions, and IL-17 signaling pathway genes (\n                      <jats:italic>Il17b<\/jats:italic>\n                      ,\n                      <jats:italic>Mmp3<\/jats:italic>\n                      and\n                      <jats:italic>Lcn2<\/jats:italic>\n                      ) under normoxia, and downregulation of proliferative genes\n                      <jats:italic>Pbk\/Topk<\/jats:italic>\n                      and\n                      <jats:italic>Racgap1<\/jats:italic>\n                      under hypoxia. Hypoxia alone downregulated all these genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The distinct transcriptional effects observed under normoxia and hypoxia highlight the importance of accounting for oxygen tension in cartilage studies. Potential inflammation-associated gene expression responses to TIMP-3 should be considered in its therapeutic development for arthritic disease and may inform optimization of treatment strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1794078","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T05:36:48Z","timestamp":1773207408000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploratory transcriptomic analysis of mouse articular cartilage in response to tissue inhibitor of metalloproteinase 3 identifies inflammation-associated gene expression changes"],"prefix":"10.3389","volume":"17","author":[{"given":"Manuela","family":"Mengozzi","sequence":"first","affiliation":[{"name":"Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Sussex","place":["Brighton, United 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