{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T20:42:03Z","timestamp":1765485723545},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,8,16]],"date-time":"2013-08-16T00:00:00Z","timestamp":1376611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Osteoclasts are multinucleated cells responsible for the resorption of bone and other mineralized tissues during development, physiological remodeling, and pathological bone loss. Osteoclasts have the ability to resorb substrate while concurrently migrating. However, the subcellular processes underlying migration are not well understood. It has been proposed that, in other cell types, cytosolic free Ca2+ concentration ([Ca2+]i) regulates cell protrusion as well as retraction. Integration of these distinct events would require precise spatiotemporal patterning of subcellular Ca2+. The large size of osteoclasts offers a unique opportunity to monitor patterns of Ca2+ during cell migration. We used ratiometric imaging to map [Ca2+]i within rat and mouse osteoclasts. Migration was characterized by lamellipodial outgrowth at the leading edge, along with intermittent retraction of the uropod. Migrating osteoclasts displayed elevation of [Ca2+]i in the uropod, that began prior to retraction. Dissipation of this [Ca2+]i gradient by loading osteoclasts with the Ca2+ chelator BAPTA abolished uropod retraction, on both glass and mineralized substrates. In contrast, elevation of [Ca2+]i using ionomycin initiated prompt uropod retraction. To investigate downstream effectors, we treated cells with calpain inhibitor-1, which impaired uropod retraction. In contrast, lamellipodial outgrowth at the leading edge of osteoclasts was unaffected by any of these interventions, indicating that the signals regulating outgrowth are distinct from those triggering retraction. The large size of mature, multinucleated osteoclasts allowed us to discern a novel spatiotemporal pattern of Ca2+ involved in cell migration. Whereas localized elevation of Ca2+ is necessary for uropod retraction, lamellipod outgrowth is independent of Ca2+\u2014a heretofore unrecognized degree of specificity underlying the regulation of osteoclast migration. \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2068","type":"journal-article","created":{"date-parts":[[2013,8,16]],"date-time":"2013-08-16T17:24:56Z","timestamp":1376673896000},"page":"725-734","source":"Crossref","is-referenced-by-count":15,"title":["Subcellular Elevation of Cytosolic Free Calcium Is Required for Osteoclast Migration"],"prefix":"10.1093","volume":"29","author":[{"given":"Benjamin D","family":"Wheal","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & DentistryThe University of Western OntarioLondonCanada"},{"name":"Graduate Program in NeuroscienceThe University of Western OntarioLondonCanada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan J","family":"Beach","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & DentistryThe University of Western OntarioLondonCanada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natsuko","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Nihon University School of DentistryTokyoJapan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S Jeffrey","family":"Dixon","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & DentistryThe University of Western OntarioLondonCanada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen M","family":"Sims","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & DentistryThe University of Western 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