{
  "abstract": "Bisphosphonates (BPs) are the most widely used anti-resorptive agents and first-line drugs for managing bone-related diseases, such as osteoporosis, Paget disease of bone, and bone metastatic cancer. BPs are known to inhibit osteoclasts’ functions, and recent studies have highlighted the importance of macroautophagy/autophagy in osteoclasts. However, the involvement of autophagy in BP-mediated inhibition of osteoclast functions remains unclear. In this study, we showed that BPs inhibit the bone resorptive functions of osteoclasts by blocking autophagy. At the non-apoptotic doses, zoledronic acid (ZOL) inhibited autophagy by blocking autophagic flux and delaying the degradation of autophagy-related proteins. ZOL also prevented the cleavage and secretion of secretory proteins such as CTSK, ACP5/TRAP, and MMP9 essential for bone resorption. Mechanistically, ZOL inhibits the prenylation of the RAB7 small GTPase, a key protein that is required for autolysosome formation. In vivo studies showed that osteoclast-specific rab7 conditional knockout mice exhibited osteopetrotic phenotypes. These findings provide insights into how BPs disrupt osteoclast function by blocking autophagy and suggest that targeting autophagy in osteoclasts could be a potential therapeutic approach for bone-related diseases.\n\nAbbreviations: ACP5/TRAP: acid phosphatase 5, tartrate resistant, ATG: autophagy related, 54 BafA1: bafilomycin A1, BECN1: beclin 1, BMM: bone marrow-derived macrophage, CQ: 55 chloroquine, CSF1/M-CSF: colony stimulating factor 1, CTSK: cathepsin K, CTX-I: C-terminal 56 telopeptide of type I collagen, FPPS: farnesyl pyrophosphate synthase, GFP: green fluorescent 57 protein, GGTI: geranylgeranyltransferase I inhibitor, LAMP1: lysosome associated membrane 58 protein 1, MAP1LC3/LC3: microtubule associated protein 1 light chain 3, MMP9: matrix 59 metallopeptidase 9, N-BPs: nitrogen-containing bisphosphonates, P1NP: procollagen type I N- 60 terminal propeptide, PGGT1B: protein geranylgeranyl transferase type I subunit beta, RABGGTB: 61 Rab geranylgeranyltransferase subunit beta, RFP: red fluorescent protein, SQSTM1/p62: 62 sequestosome 1, TNFSF11/RANKL: TNF superfamily member 11, ZOL: zoledronic acid,",
  "abstract_shown": true,
  "affiliations": [
    "The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA",
    "Division of Preventive and Restorative Sciences, UCLA School of Dentistry, Los Angeles, CA, USA",
    "Section of Biosystems and Function, UCLA School of Dentistry, Los Angeles, CA, USA",
    "Institute for Oral Science, Department of Orthodontics, Matsumoto Dental University, Nagano, Japan",
    "The Pasarow Mass Spectrometry Laboratory, the Jane and Terry Semel Institute for Neuroscience and Human Behavior, UCLA David Geffen School of Medicine, Los Angeles, CA, USA",
    "UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA",
    "UCLA David Geffen School of Medicine, Los Angeles, CA, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Sol Kim"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Vadim Goldshteyn"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Atsushi Arai"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Eun-Bin Bae"
    },
    {
      "affs": [
        4
      ],
      "name": "Julian Whitelegge"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Ki-Hyuk Shin"
    },
    {
      "affs": [
        0,
        5,
        6
      ],
      "name": "No-Hee Park"
    },
    {
      "affs": [
        0,
        1,
        2,
        5
      ],
      "name": "Reuben H. Kim",
      "orcid": "0000-0001-5635-7728"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8gmp9wv25547e.bib",
  "cited_by": 1,
  "doi": "10.1080/15548627.2026.2691880",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712003/",
  "id": "8gmp9wv25547e",
  "issns": [
    "1554-8627",
    "1554-8635"
  ],
  "landing_url": "https://doi.org/10.1080/15548627.2026.2691880",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "heading",
      "Research Paper"
    ],
    [
      "openalex",
      "1312|Bone Metabolism and Diseases"
    ]
  ],
  "openalex": "W7165127774",
  "pdf_url": null,
  "pmcid": "PMC13712003",
  "pmid": "42316434",
  "published": "2026-06-28",
  "publisher": "Taylor & Francis",
  "ris": "https://research.draconitic.com/paper/8gmp9wv25547e.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:41Z",
      "native_id": "PMC13712003",
      "source": "pmc",
      "url": "https://doi.org/10.1080/15548627.2026.2691880"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Bone Metabolism and Diseases",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Bisphosphonate zoledronic acid blocks secretory autophagy and inhibits bone resorptive functions in osteoclasts",
  "title_text": "Bisphosphonate zoledronic acid blocks secretory autophagy and inhibits bone resorptive functions in osteoclasts",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:41Z",
  "url": "https://research.draconitic.com/paper/8gmp9wv25547e",
  "venue": "Autophagy",
  "versions": []
}