{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T01:07:32Z","timestamp":1778980052707,"version":"3.51.4"},"reference-count":63,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE017102; R01DE022765"],"award-info":[{"award-number":["R01DE017102; R01DE022765"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Although Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      signaling and metabolism have been identified as key determinants for the development of Sj\u00f6gren disease (SjD), the intricate connection between them and salivary gland physiology remains poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Fluorescence\u2010based Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging, RNA sequencing, and mitochondrial activity were used to investigate the effects of circadian rhythm and salivary gland dysfunction. Critical findings were confirmed by studying mouse models of SjD and human salivary gland samples.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified that Ca\n                      <jats:sup>2+<\/jats:sup>\n                      entry is essential in modulating\n                      <jats:italic>Clock<\/jats:italic>\n                      genes and circadian rhythm, which also modulate salivary gland secretion and the expression of\n                      <jats:italic>Stim<\/jats:italic>\n                      and\n                      <jats:italic>Orai<\/jats:italic>\n                      genes. Mechanistically, our data show that Bmal2 binding in the promoter region of Stim1 modulates its expression, thereby regulating Ca\n                      <jats:sup>2+<\/jats:sup>\n                      entry and mitochondrial bioenergetics and providing cyclic rhythm\u2013mediated regulation of cellular physiology. To assess Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \u2010dependent circadian rhythms, we used diet perturbation, in which a Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \u2010deficient diet specifically impacts the\n                      <jats:italic>Clock<\/jats:italic>\n                      gene's rhythm, which was reversed by Ca\n                      <jats:sup>2+<\/jats:sup>\n                      supplementation. Circadian rhythm\u2013mediated regulation of fluid secretion, as well as STIM1 genes, was also altered in an SjD mouse model. In addition, human patients with SjD also showed dysregulation of\n                      <jats:italic>CLOCK<\/jats:italic>\n                      and\n                      <jats:italic>STIM1<\/jats:italic>\n                      genes, which could alter salivary physiology, leading to the development of the SjD phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our results provide the first comprehensive evidence of a reciprocal relationship between circadian rhythm, Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signaling, and metabolism, which is critical for cellular physiology and disease development\/progression.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        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