{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:42:30Z","timestamp":1791895350166,"version":"4.3.4"},"reference-count":65,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T00:00:00Z","timestamp":1731110400000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771092"],"award-info":[{"award-number":["81771092"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970910"],"award-info":[{"award-number":["81970910"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bisphosphonates (BPs) are the first\u2010line treatment to stop bone resorption in diseases, including osteoporosis, Paget's disease, multiple myeloma and bone metastases of cancer. However, BPs\u2010related osteonecrosis of the jaw (BRONJ), characterized by local inflammation and jawbone necrosis, is a severe intractable complication. The cumulative inflammatory burden often accompanies impaired lymphatic drainage, but its specific impact on BRONJ and the underlying mechanisms remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The mouse BRONJ model was established to assess the integrity and drainage function of lymphatic vessels by tissue clearing techniques, injected indocyanine green lymphatic clearance assay, flow cytometry analysis and histopathological staining. RNA sequencing, metabolome analysis, transmission electron microscopy and Western blotting were utilized to analyze the impacts of Zoledronate acid (ZA) on endoplasmic reticulum stress (ERS) and function of lymphatic endothelial cells (LECs). By constructing\n                      <jats:italic>\n                        Lyve1\n                        <jats:sup>creERT<\/jats:sup>\n                        ; SIRT6\n                        <jats:sup>f\/f<\/jats:sup>\n                      <\/jats:italic>\n                      and\n                      <jats:italic>\n                        Lyve1\n                        <jats:sup>creERT<\/jats:sup>\n                        ; ATG5\n                        <jats:sup>f\/f<\/jats:sup>\n                      <\/jats:italic>\n                      mice, we evaluated the role of ERS\u2010induced LECs apoptosis in the progression of BRONJ. Additionally, we developed a nanoparticle\u2010loaded ZA and rapamycin (ZDPR) to enhance autophagy and evaluated its potential in mitigating BRONJ.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The mouse BRONJ model displayed impaired lymphatic drainage, accompanied by significant local inflammation and bone necrosis. The prolonged stimulation of ZA resulted in the extension of ERS and the inhibition of autophagy in LECs, ultimately leading to apoptosis. Mechanistically, ZA activated XBP1s through the NAD\n                      <jats:sup>+<\/jats:sup>\n                      \/SIRT6 pathway, initiating ERS\u2010induced apoptosis in LECs. The conditional knockout mouse models demonstrated that the deletion of\n                      <jats:italic>SIRT6<\/jats:italic>\n                      or\n                      <jats:italic>ATG5<\/jats:italic>\n                      significantly worsened lymphatic drainage and inflammatory infiltration in BRONJ. Additionally, the innovative nanoparticle ZDPR alleviated ERS\u2010apoptosis in LECs and enhanced lymphatic function, facilitating inflammation resolution.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our study has elucidated the role of the NAD\n                      <jats:sup>+<\/jats:sup>\n                      \/SIRT6\/XBP1s pathway in ERS\u2010induced apoptosis in ZA\u2010treated LECs, and further confirmed the therapeutic potential of ZDPR in restoring endothelial function and improving lymphatic drainage, thereby effectively mitigating BRONJ.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Bisphosphonate\u2010induced lymphatic drainage impairment exacerbates bone necrosis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Zoledronate acid triggers endoplasmic reticulum stress and apoptosis in lymphatic endothelial cells via the NAD+\/SIRT6\/XBP1s pathway.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Novel nanoparticle\u2010loaded Zoledronate acid and rapamycin enhances autophagy, restores lymphatic function, and mitigates bisphosphonates\u2010related osteonecrosis of the jaw progression.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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