{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:55:10Z","timestamp":1790697310035,"version":"4.1.0"},"reference-count":78,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T00:00:00Z","timestamp":1590019200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bisphosphonate therapy has become a popular treatment for osteoporosis, Paget\u2019s disease, multiple myeloma, osteogenesis imperfecta, myocardial infarction, and cancer despite its serious side effects. Bisphosphonate-induced molecular signaling changes in cells are still not clearly elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>As bisphosphonates are primarily engulfed by macrophages, we treated RAW 264.7 cells (a murine macrophage cell line) with pamidronate and investigated global protein expressional changes in cells by immunoprecipitation high performance liquid chromatography (IP-HPLC) using 218 antisera.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Pamidronate upregulated proliferation-activating proteins associated with p53\/Rb\/E2F and Wnt\/\u03b2-catenin pathways, but downregulated the downstream of RAS signaling, pAKT1\/2\/3, ERK-1, and p-ERK-1, and subsequently suppressed cMyc\/MAX\/MAD network. However, in situ proliferation index of pamidronate-treated RAW264.7 cells was slightly increased by 3.2% vs. non-treated controls. Pamidronate-treated cells showed increase in the expressions of histone- and DNA methylation-related proteins but decrease of protein translation-related proteins. NFkB signaling was also suppressed as indicated by the down-regulations of p38 and p-p38 and the up-regulation of mTOR, while the protein expressions related to cellular protection, HSP-70, NRF2, JNK-1, and LC3 were upregulated. Consequently, pamidronate downregulated the protein expressions related to immediate inflammation,cellular differentiation, survival, angiogenesis, and osteoclastogenesis, but upregulated PARP-1 and FAS-mediated apoptosis proteins. These observations suggest pamidronate affects global protein expressions in RAW 264.7 cells by stimulating cellular proliferation, protection, and apoptosis but suppressing immediate inflammation, differentiation, osteoclastogenesis, and angiogenesis. Accordingly, pamidronate appears to affect macrophages in several ways eliciting not only its therapeutic effects but also atypical epigenetic modification, protein translation, RAS and NFkB signalings. Therefore, our observations suggest pamidronate-induced protein expressions are dynamic, and the affected proteins should be monitored by IP-HPLC to achieve the therapeutic goals during treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7717\/peerj.9202","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T04:47:50Z","timestamp":1590036470000},"page":"e9202","source":"Crossref","is-referenced-by-count":12,"title":["Extensive protein expression changes induced by pamidronate in RAW 264.7 cells as determined by IP-HPLC"],"prefix":"10.7717","volume":"8","author":[{"given":"Sang Shin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, Gangneung, Gangwondo, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6916-0489","authenticated-orcid":true,"given":"Soung Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5787-7052","authenticated-orcid":true,"given":"Yeon Sook","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Dental Hygiene, College of Health & Medical Sciences, Cheongju University, Cheongju, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk Keun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, Gangneung, Gangwondo, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4443","published-online":{"date-parts":[[2020,5,21]]},"reference":[{"issue":"3","key":"10.7717\/peerj.9202\/ref-1","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1185\/030079908X260899","article-title":"A review of Paget\u2019s disease of bone with a focus on the efficacy and safety of zoledronic acid 5 mg","volume":"24","author":"Abelson","year":"2008","journal-title":"Current Medical Research and Opinion"},{"key":"10.7717\/peerj.9202\/ref-2","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.bone.2015.08.002","article-title":"Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone","volume":"81","author":"Acevedo","year":"2015","journal-title":"Bone"},{"issue":"3","key":"10.7717\/peerj.9202\/ref-3","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1111\/bcp.13147","article-title":"Efficacy of bisphosphonate as an adjunct to nonsurgical periodontal therapy in the management of periodontal disease: a systematic review","volume":"83","author":"Akram","year":"2017","journal-title":"British Journal of Clinical Pharmacology"},{"key":"10.7717\/peerj.9202\/ref-4","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.bonr.2017.02.002","article-title":"Low dose effect of bisphosphonates on hMSCs osteogenic response to titanium surface in vitro","volume":"6","author":"Alqhtani","year":"2017","journal-title":"Bone Reports"},{"issue":"6","key":"10.7717\/peerj.9202\/ref-5","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.reuma.2017.04.002","article-title":"Recurrent multifocal osteomyelitis in children: experience in a tertiary care center","volume":"14","author":"Ariza Jimenez","year":"2018","journal-title":"Reumatologia Clinica"},{"issue":"2","key":"10.7717\/peerj.9202\/ref-6","doi-asserted-by":"publisher","first-page":"e38","DOI":"10.1111\/clr.12526","article-title":"What is the impact of bisphosphonate therapy upon dental implant survival? 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