Mature bone-resorbing osteoclasts (OCs) mediate excessive bone loss seen in several bone disorders, including osteoporosis. Here, we showed that reveromycin A (RM-A), a small natural product with three carboxylic groups in its structure, induced apoptosis specifically in OCs, but not in OC progenitors, nonfunctional osteoclasts, or osteoblasts. RM-A inhibited protein synthesis in OCs by selectively blocking enzymatic activity of isoleucyl-tRNA synthetase. The proapoptotic effect of RM-A was inhibited by neutralization or disruption of the acidic microenvironment, a prominent characteristic of OCs. RM-A was incorporated in OCs but not in nonfunctional osteoclasts and OC progenitors in neutral culture medium. Effects of RM-A on OC apoptosis increased under acidic culture conditions. RM-A not only was incorporated, but also induced apoptosis in OC progenitors in acidic culture medium. RM-A inhibited osteoclastic pit formation, decreased prelabeled (45)Ca release in organ cultures, and antagonized increased bone resorption in ovariectomized mice. These results suggested that preventive effects of RM-A on bone resorption in vitro and in vivo were caused by apoptosis through inhibition of isoleucyl-tRNA synthetase in OCs and that specific sensitivity of OCs to RM-A was due to the acidic microenvironment, which increased cell permeability of RM-A by suppressing dissociation of protons from carboxylic acid moieties, making them less polar. This unique mechanism suggested that RM-A might represent a type of therapeutic agent for treating bone disorders associated with increased bone loss.<\/p>\n","protected":false},"excerpt":{"rendered":"
Mature bone-resorbing osteoclasts (OCs) mediate excessive bone loss seen in several bone disorders, including osteoporosis. Here, we showed that reveromycin<\/p>\n","protected":false},"author":22,"parent":0,"menu_order":0,"template":"","format":"standard","meta":{"_acf_changed":false},"tags":[],"thema":[5866,5920],"produktgruppe":[5825],"literatur_kategorie":[7223],"class_list":["post-163176","literatur","type-literatur","status-publish","format-standard","hentry","thema-diagnostics-using-leonardo-pqct","thema-pre-clinical-research","produktgruppe-pqct-en","literatur_kategorie-pre-clinical-studies"],"acf":[],"_links":{"self":[{"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/literatur\/163176","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/literatur"}],"about":[{"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/types\/literatur"}],"author":[{"embeddable":true,"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/users\/22"}],"version-history":[{"count":0,"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/literatur\/163176\/revisions"}],"wp:attachment":[{"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/media?parent=163176"}],"wp:term":[{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/tags?post=163176"},{"taxonomy":"thema","embeddable":true,"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/thema?post=163176"},{"taxonomy":"produktgruppe","embeddable":true,"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/produktgruppe?post=163176"},{"taxonomy":"literatur_kategorie","embeddable":true,"href":"https:\/\/stratec-med.com\/en\/wp-json\/wp\/v2\/literatur_kategorie?post=163176"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}