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

  • Autophagy. 2026 Jun 28:1-13. doi: 10.1080/15548627.2026.2691880.
Sol Kim  1  2  3 ,  Vadim Goldshteyn  1  2 ,  Atsushi Arai  1  4 ,  Eun-Bin Bae  1  2 ,  Julian Whitelegge  5 ,  Ki-Hyuk Shin  1  3 ,  No-Hee Park  1  6  7 ,  Reuben H Kim  1  2  3  6
Affiliations
  • 1. The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
  • 2. Division of Preventive and Restorative Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
  • 3. Section of Biosystems and Function, UCLA School of Dentistry, Los Angeles, CA, USA.
  • 4. Institute for Oral Science, Department of Orthodontics, Matsumoto Dental University, Nagano, Japan.
  • 5. 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.
  • 6. UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
  • 7. UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
PMID: 42316434 DOI: 10.1080/15548627.2026.2691880
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.

Keywords
Autophagy; RAB7; bisphosphonate; osteoclasts; prenylation.
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