Bonewald, L. F. The amazing osteocyte. J. Bone Min. Res. 26, 229–238 (2011).

Article  CAS  Google Scholar 

Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).

Article  CAS  PubMed  Google Scholar 

Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nat. Med. 17, 1235–1241 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xiong, J. & O'Brien, C. A. Osteocyte RANKL: new insights into the control of bone remodeling. J. Bone Min. Res. 27, 499–505 (2012).

Article  CAS  Google Scholar 

Xiong, J. et al. Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS One 10, e0138189 (2015).

Article  PubMed  PubMed Central  Google Scholar 

Tsukasaki, M. & Takayanagi, H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat. Rev. Immunol. 19, 626–642 (2019).

Article  CAS  PubMed  Google Scholar 

Fujiwara, Y. et al. RANKL (Receptor Activator of NFκB Ligand) produced by osteocytes is required for the increase in B cells and bone loss caused by estrogen deficiency in mice. J. Biol. Chem. 291, 24838–24850 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xiong, J. et al. Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency. Bone 66, 146–154 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wein, M. N. Parathyroid hormone signaling in osteocytes. J. Bone Min. Res. 2, 22–30 (2018).

CAS  Google Scholar 

O'Brien, C. A. et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145, 1835–1841 (2004).

Article  CAS  PubMed  Google Scholar 

Piemontese, M., Xiong, J., Fujiwara, Y., Thostenson, J. D. & O'Brien, C. A. Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. Am. J. Physiol. Endocrinol. Metab. 311, E587–E593 (2016).

Article  PubMed  PubMed Central  Google Scholar 

Weinstein, R. S. et al. Osteoprotegerin prevents glucocorticoid-induced osteocyte apoptosis in mice. Endocrinology 152, 3323–3331 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tatsumi, S. et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 5, 464–475 (2007).

Article  CAS  PubMed  Google Scholar 

Cheung, W. Y. et al. Pannexin-1 and P2X7-Receptor are required for apoptotic osteocytes in fatigued bone to trigger RANKL production in neighboring bystander osteocytes. J. Bone Min. Res. 31, 890–899 (2016).

Article  CAS  Google Scholar 

Andreev, D. et al. Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin. J. Clin. Investig. 130, 4811–4830 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kim, H. N. et al. Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence. JCI Insight 5, e138815 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Jilka, R. L. et al. Dysapoptosis of osteoblasts and osteocytes increases cancellous bone formation but exaggerates cortical porosity with age. J. Bone Min. Res. 29, 103–117 (2014).

Article  CAS  Google Scholar 

Onal, M. et al. Unique distal enhancers linked to the mouse Tnfsf11 gene direct tissue-specific and inflammation-induced expression of RANKL. Endocrinology 157, 482–496 (2016).

Article  CAS  PubMed  Google Scholar 

Fu, Q., Manolagas, S. C. & O'Brien, C. A. Parathyroid hormone controls receptor activator of NF-kappaB ligand gene expression via a distant transcriptional enhancer. Mol. Cell Biol. 26, 6453–6468 (2006).

Article  CAS  PubMed  PubMed Central  Google Scholar 

O'Brien, C. A. Control of RANKL gene expression. Bone 46, 911–919 (2010).

Article  CAS  PubMed  Google Scholar 

Yan, M. et al. ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Nat. Immunol. 23, 1330–1341 (2022).

Article  CAS  PubMed  Google Scholar 

ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

Shen, Y. et al. A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116–120 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Holwerda, S. J. & de Laat, W. CTCF: the protein, the binding partners, the binding sites and their chromatin loops. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, 20120369 (2013).

Article  PubMed  PubMed Central  Google Scholar 

Kim, S. K. Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS One 13, e0200785 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Morris, J. A. et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat. Genet. 51, 258–266 (2019).

Article  CAS  PubMed  Google Scholar 

Kemp, J. P. et al. Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment. PLoS Genet. 10, e1004423 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Kichaev, G. et al. Leveraging Polygenic Functional Enrichment to Improve GWAS Power. Am. J. Hum. Genet. 104, 65–75 (2019).

Article  CAS  PubMed  Google Scholar 

Wang, J. S. et al. Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin. Nat. Commun. 12, 6271 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

Article  CAS  PubMed  Google Scholar 

Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

Article  CAS  PubMed  Google Scholar 

Kang, C. et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612 (2015).

Article  PubMed  PubMed Central  Google Scholar 

Hu, Y. et al. RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss. EMBO Rep. 22, e52481 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yu, W. et al. Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss. J. Clin. Investig. 131, e140214 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Levine, M. Transcriptional enhancers in animal development and evolution. Curr. Biol. 20, R754–R763 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

St John, H. C. et al. The osteoblast to osteocyte transition: epigenetic changes and response to the vitamin D3 hormone. Mol. Endocrinol. 28, 1150–1165 (2014).

Article  Google Scholar 

Visel, A., Minovitsky, S., Dubchak, I. & Pennacchio, L. A. VISTA Enhancer Browser–a database of tissue-specific human enhancers. Nucleic Acids Res. 35, D88–D92 (2007).

Article  CAS  PubMed  Google Scholar 

Wen, A. Y., Sakamoto, K. M. & Miller, L. S. The role of the transcription factor CREB in immune function. J. Immunol. 185, 6413–6419 (2010).

Article  CAS  PubMed  Google Scholar 

Frost, H. M. In vivo osteocyte death. J. Bone Jt. Surg. Am. 42-a, 138–143 (1960).

Article  CAS