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TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remain to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes and also exhibit unique co\u2010regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)\u20101\u2010responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro\u2010chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in\u00a0vitro. These findings emphasize the presence of a broad \u201cmechanome\u201d with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL\u20101\u2010induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.<\/jats:p>","DOI":"10.1096\/fj.202400883r","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T11:38:56Z","timestamp":1720006736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["The chondrocyte \u201cmechanome\u201d: Activation of the mechanosensitive ion channels\n                    <scp>TRPV4<\/scp>\n                    and\n                    <scp>PIEZO1<\/scp>\n                    drives unique transcriptional signatures"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0856-3188","authenticated-orcid":false,"given":"Robert","family":"Nims","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University School of Medicine  St. Louis Missouri USA"},{"name":"Shriners Hospitals for Children\u2014Saint Louis  St. Louis Missouri USA"},{"name":"Center of Regenerative Medicine Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9088-641X","authenticated-orcid":false,"given":"Daniel R.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University School of Medicine  St. Louis Missouri USA"},{"name":"Shriners Hospitals for Children\u2014Saint Louis  St. Louis Missouri USA"},{"name":"Center of Regenerative Medicine Washington University School of Medicine  St. 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