{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T13:44:40Z","timestamp":1772545480214,"version":"3.50.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Bisphosphonates (BPs), widely used anti-resorptive agents for osteoporosis and cancer-related bone metastasis, can paradoxically contribute to medication-related osteonecrosis of the jaw (MRONJ). Our previous work showed that periodontal ligament stem cells (PDLSCs) from MRONJ patients display severely impaired osteogenesis; however, how BPs directly regulate PDLSC function remains unclear. In this study, human PDLSCs were exposed to graded concentrations of zoledronate (ZOL, 0.01\u201310\u00a0\u03bcM) to characterize dose-dependent effects on cell viability, apoptosis, and osteogenic differentiation. High-dose ZOL markedly reduced proliferation, induced apoptosis, and strongly inhibited osteogenesis. In contrast, low-dose ZOL promoted osteogenic differentiation\n                    <jats:italic>in vitro<\/jats:italic>\n                    , enhanced mineralization, and increased ectopic bone formation\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Transcriptomic and molecular analyses revealed that ZOL activated Wnt\/\u03b2-catenin and MAPK signaling, and blockade of either pathway attenuated the osteogenic enhancement. These findings demonstrate a double-edged-sword effect of BPs on PDLSCs: low-dose ZOL enhances osteogenesis through coordinated activation of Wnt\/\u03b2-catenin and MAPK pathways, whereas high-dose exposure is cytotoxic and suppresses regenerative potential. The results underscore the necessity of precise BP dose control to maximize periodontal regeneration while minimizing MRONJ risk.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1752252","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T09:24:16Z","timestamp":1772529856000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Double-edged-sword effect of bisphosphonates on the osteogenic differentiation of human periodontal ligament stem cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Mengyu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Oral-maxillofacial Head and Neck Oncology, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"College of Stomatology, Shanghai Jiao Tong University","place":["Shanghai, China"]},{"name":"National Center for Stomatology, National 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