ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2020
Apoptotic Osteocytes Induce RANKL Production in Bystanders via Purinergic Signaling and Activation of Pannexin Channels.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- Unraveling stress fractures: from cellular and molecular mechanisms to therapeutic approaches.Journal of orthopaedic translation · 2026Review
- Apoptosis of Mdm2-deficient osteocytes enhances osteogenesis through TRPM8-enriched apoptotic vesicles.Bone research · 2026Article
- Periodontitis as a Model for Inflammatory Uncoupling of Bone Remodeling.Journal of periodontal research · 2026Review
- Denosumab discontinuation in the clinic: implications of rebound bone turnover and emerging strategies to prevent bone loss and fractures.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2025Review
- Mechanosignaling in Osteoporosis: When Cells Feel the Force.International journal of molecular sciences · 2025Review
- Osteocytes function as biomechanical signaling hubs bridging mechanical stress sensing and systemic adaptation.Frontiers in physiology · 2025Review
- Pannexins in the musculoskeletal system: new targets for development and disease progression.Bone research · 2024Review
- Connexin 43 in the function and homeostasis of osteocytes: a narrative review.Annals of joint · 2024Review
- Connexin 43 and cell culture substrate differentially regulate OCY454 osteocytic differentiation and signaling to primary bone cells.American journal of physiology. Cell physiology · 2023Article
- SP7: from Bone Development to Skeletal Disease.Current osteoporosis reports · 2023Review
- Focused Low-Intensity Pulsed Ultrasound (FLIPUS) Mitigates Apoptosis of MLO-Y4 Osteocyte-like Cells.Bioengineering (Basel, Switzerland) · 2023Article
- Oxidative Stress and Natural Antioxidants in Osteoporosis: Novel Preventive and Therapeutic Approaches.Antioxidants (Basel, Switzerland) · 2023Review
- The osteocyte and its osteoclastogenic potential.Frontiers in endocrinology · 2023Review
- Osteoimmunology in Periodontitis: Local Proteins and Compounds to Alleviate Periodontitis.International journal of molecular sciences · 2022Review
- Bone stress injuries.Nature reviews. Disease primers · 2022Review
- Effect of Oxidative Stress-Induced Apoptosis on Active FGF23 Levels in MLO-Y4 Cells: The Protective Role of 17-β-Estradiol.International journal of molecular sciences · 2022Article
- Osteocytes and Weightlessness.Current osteoporosis reports · 2021Review
- Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin.Nature communications · 2021Article
- Potential Role of Perilacunar Remodeling in the Progression of Osteoporosis and Implications on Age-Related Decline in Fracture Resistance of Bone.Current osteoporosis reports · 2021Review
- Update on the effects of microgravity on the musculoskeletal system.NPJ microgravity · 2021Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Localized apoptosis of osteocytes, the tissue-resident cells within bone, occurs with fatigue microdamage and activates bone resorption. Osteoclasts appear to target and remove dying osteocytes, resorbing damaged bone matrix as well. Osteocyte apoptosis similarly activates bone resorption with estrogen loss and in disuse. Apoptotic osteocytes trigger viable neighbor (ie, bystander) osteocytes to produce RANKL, the cytokine required for osteoclast activation. Signals from apoptotic osteocytes that trigger this bystander RANKL expression remain obscure. Studying signaling among osteocytes has been hampered by lack of in vitro systems that model the limited communication among osteocytes in vivo (ie, via gap junctions on cell processes and/or paracrine signals through thin pericellular fluid spaces around osteocytes). Here, we used a novel multiscale fluidic device (the Macro-micro-nano, or Mμn) that reproduces these key anatomical features. Osteocytes in discrete compartments of the device communicate only via these limited pathways, which allows assessment of their roles in triggering osteocytes RANKL expression. Apoptosis of MLOY-4 osteocytes in the Mμn device caused increased osteocyte RANKL expression in the neighboring compartment, consistent with in vivo findings. This RANKL upregulation in bystander osteocytes was prevented by blocking Pannexin 1 channels as well as its ATP receptor. ATP alone caused comparable RANKL upregulation in bystander osteocytes. Finally, blocking Connexin 43 gap junctions did not abolish osteocyte RANKL upregulation, but did alter the distribution of RANKL expressing bystander osteocytes. These findings point to extracellular ATP, released from apoptotic osteocytes via Panx1 channels, as a major signal for triggering bystander osteocyte RANKL expression and activating bone remodeling. © 2020 American Society for Bone and Mineral Research.
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Registered trials
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