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Peer-reviewedCC BY 4.0Autophagy

Bisphosphonate zoledronic acid blocks secretory autophagy and inhibits bone resorptive functions in osteoclasts

  • Sol Kim1,2,3
  • Vadim Goldshteyn1,2
  • Atsushi Arai1,4
  • Eun-Bin Bae1,2
  • Julian Whitelegge5
  • Ki-Hyuk Shin1,3
  • No-Hee Park1,6,7
  • Reuben H. Kim1,2,3,6
7 affiliations
  1. 1The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA
  2. 2Division of Preventive and Restorative Sciences, UCLA School of Dentistry, Los Angeles, CA, USA
  3. 3Section of Biosystems and Function, UCLA School of Dentistry, Los Angeles, CA, USA
  4. 4Institute for Oral Science, Department of Orthodontics, Matsumoto Dental University, Nagano, Japan
  5. 5The 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
  6. 6UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
  7. 7UCLA David Geffen School of Medicine, Los Angeles, CA, USA
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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.

Abbreviations: 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,

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Cite

BibTeXRIS
BibTeX
@article{kim2026bisphosphonate,
  title = {{Bisphosphonate zoledronic acid blocks secretory autophagy and inhibits bone resorptive functions in osteoclasts}},
  author = {Sol Kim and Vadim Goldshteyn and Atsushi Arai and Eun-Bin Bae and Julian Whitelegge and Ki-Hyuk Shin and No-Hee Park and Reuben H. Kim},
  journal = {Autophagy},
  year = {2026},
  month = jun,
  doi = {10.1080/15548627.2026.2691880},
  url = {https://doi.org/10.1080/15548627.2026.2691880},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Bisphosphonate zoledronic acid blocks secretory autophagy and inhibits bone resorptive functions in osteoclasts
AU  - Sol Kim
AU  - Vadim Goldshteyn
AU  - Atsushi Arai
AU  - Eun-Bin Bae
AU  - Julian Whitelegge
AU  - Ki-Hyuk Shin
AU  - No-Hee Park
AU  - Reuben H. Kim
PY  - 2026
DA  - 2026/06/28
JO  - Autophagy
DO  - 10.1080/15548627.2026.2691880
UR  - https://doi.org/10.1080/15548627.2026.2691880
AB  - 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.  Abbreviations: 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,
SN  - 1554-8627
SN  - 1554-8635
ER  -