{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:38:33Z","timestamp":1790710713856,"version":"4.1.0"},"reference-count":122,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2016,12,6]],"date-time":"2016-12-06T00:00:00Z","timestamp":1480982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japanese Ministry of Education, Culture, Sports, Science and Technology, Japan","award":["26221310"],"award-info":[{"award-number":["26221310"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation of P53 and RB is involved in the pathogenesis of osteosarcomas, the deletion of p53 and inactivation of Rb are insufficient to enhance chondrocyte proliferation, indicating the presence of multiple inhibitory mechanisms against sarcomagenesis in chondrocytes. The inflammatory processes induced by mechanical injury and chondrocyte death through the release of danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of posttraumatic osteoarthritis. The overexpression of BCLXL increases bone volume with a normal structure and maintains bone during aging by inhibiting osteoblast apoptosis. p53 inhibits osteoblast proliferation and enhances osteoblast apoptosis, thereby reducing bone formation, but also exerts positive effects on osteoblast differentiation through the Akt\u2013FoxOs pathway. Apoptotic osteocytes release ATP, which induces the receptor activator of nuclear factor \u03ba-B ligand (Rankl) expression and osteoclastogenesis, from pannexin 1 channels. Osteocyte death ultimately results in necrosis; DAMPs are released to the bone surface and promote the production of proinflammatory cytokines, which induce Rankl expression, and osteoclastogenesis is further enhanced.<\/jats:p>","DOI":"10.3390\/ijms17122045","type":"journal-article","created":{"date-parts":[[2016,12,6]],"date-time":"2016-12-06T10:07:17Z","timestamp":1481018837000},"page":"2045","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":164,"title":["Cell Death in Chondrocytes, Osteoblasts, and Osteocytes"],"prefix":"10.3390","volume":"17","author":[{"given":"Toshihisa","family":"Komori","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1101\/gad.1174704","article-title":"Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog","volume":"18","author":"Yoshida","year":"2004","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/(SICI)1097-0177(199904)214:4<279::AID-AJA1>3.0.CO;2-W","article-title":"Maturational disturbance of chondrocytes in Cbfa1-deficient mice","volume":"214","author":"Inada","year":"1999","journal-title":"Dev. Dyn."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1101\/gad.13.16.2072","article-title":"Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation","volume":"13","author":"Hammerschmidt","year":"1999","journal-title":"Genes Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1053\/joca.2002.0860","article-title":"Runx2 expression and action in chondrocytes are regulated by retinoid signaling and parathyroid hormone-related peptide (PTHrP)","volume":"11","author":"Iwamoto","year":"2003","journal-title":"Osteoarthr. Cartil."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.yexcr.2004.05.025","article-title":"Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway","volume":"299","author":"Li","year":"2004","journal-title":"Exp. Cell Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1126\/science.273.5275.613","article-title":"Regulation of rate of cartilage differentiation by indian hedgehog and PTH-related protein","volume":"273","author":"Vortkamp","year":"1996","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1359\/jbmr.2002.17.7.1297","article-title":"Impaired vascular invasion of Cbfa1-deficient cartilage engrafted in the spleen","volume":"17","author":"Himeno","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0925-4773(01)00428-2","article-title":"Tissue specific regulation of VEGF expression during bone development requires Cbfa1\/Runx2","volume":"106","author":"Zelzer","year":"2001","journal-title":"Mech. Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00441-009-0832-8","article-title":"Regulation of bone development and extracellular matrix protein genes by Runx2","volume":"339","author":"Komori","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12097","DOI":"10.1073\/pnas.1302703111","article-title":"Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation","volume":"111","author":"Yang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhou, X., von der Mark, K., Henry, S., Norton, W., Adams, H., and de Crombrugghe, B. (2014). Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004820"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"206","DOI":"10.4161\/cc.4.2.1410","article-title":"Revisiting the \u201cCdk-centric\u201d view of the mammalian cell cycle","volume":"4","author":"Malumbres","year":"2005","journal-title":"Cell Cycle"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3852","DOI":"10.1091\/mbc.12.12.3852","article-title":"TGF\u03b2 and PTHrP control chondrocyte proliferation by activating cyclin D1 expression","volume":"12","author":"Beier","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1242\/dev.128.24.5099","article-title":"Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation","volume":"128","author":"Long","year":"2001","journal-title":"Development"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1242\/dev.00324","article-title":"Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation","volume":"130","author":"Yang","year":"2003","journal-title":"Development"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nrc3090","article-title":"Cyclin D as a therapeutic target in cancer","volume":"11","author":"Musgrove","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1101\/gad.9.19.2364","article-title":"Mice lacking cyclin D1 are small and show defects in eye and mammary gland development","volume":"9","author":"Fantl","year":"1995","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/0092-8674(95)90034-9","article-title":"Cyclin D1 provides a link between development and oncogenesis in the retina and breast","volume":"82","author":"Sicinski","year":"1995","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1101\/gad.10.13.1633","article-title":"Shared role of the pRB-related p130 and p107 proteins in limb development","volume":"10","author":"Cobrinik","year":"1996","journal-title":"Genes Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1006\/dbio.2002.0691","article-title":"p107 and p130 Coordinately regulate proliferation, Cbfa1 expression, and hypertrophic differentiation during endochondral bone development","volume":"247","author":"Rossi","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1038\/onc.2013.130","article-title":"Overexpression of Cdk6 and Ccnd1 in chondrocytes inhibited chondrocyte maturation and caused p53-dependent apoptosis without enhancing proliferation","volume":"33","author":"Ito","year":"2013","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/369669a0","article-title":"Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice","volume":"369","author":"Wang","year":"1994","journal-title":"Nature"},{"key":"ref_23","first-page":"5542","article-title":"A transgenic mouse model with cyclin D1 overexpression results in cell cycle, epidermal growth factor receptor, and p53 abnormalities","volume":"57","author":"Mueller","year":"1997","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1128\/MCB.15.7.3552","article-title":"Differential roles of two tandem E2F sites in repression of the human p107 promoter by retinoblastoma and p107 proteins","volume":"15","author":"Zhu","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Burkhart, D.L., Wirt, S.E., Zmoos, A.F., Kareta, M.S., and Sage, J. (2010). Tandem E2F binding sites in the promoter of the p107 cell cycle regulator control p107 expression and its cellular functions. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001003"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1101\/gad.11.11.1447","article-title":"pRB and p107\/p130 are required for the regulated expression of different sets of E2F responsive genes","volume":"11","author":"Hurford","year":"1997","journal-title":"Genes Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4798","DOI":"10.1038\/onc.2012.496","article-title":"Loss of pRB and p107 disrupts cartilage development and promotes enchondroma formation","volume":"32","author":"Landman","year":"2012","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.4161\/cc.25515","article-title":"Regulation of Rb family proteins by Cdk6\/Ccnd1 in growth plates","volume":"12","author":"Komori","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"50263","DOI":"10.1074\/jbc.M209181200","article-title":"G1 cyclin\/cyclin-dependent kinase-coordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression","volume":"277","author":"Calbo","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrrheum.2014.162","article-title":"Emerging regulators of the inflammatory process in osteoarthritis","volume":"11","author":"Terkeltaub","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1756-185X.2011.01618.x","article-title":"Chondrocyte apoptosis: A cause or consequence of osteoarthritis?","volume":"14","author":"Zamli","year":"2011","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.joca.2003.09.015","article-title":"Cell death in cartilage","volume":"12","author":"Kuhn","year":"2004","journal-title":"Osteoarthr. Cartil."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00441-012-1546-x","article-title":"Functions of the osteocyte network in the regulation of bone mass","volume":"352","author":"Komori","year":"2013","journal-title":"Cell Tissue Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1023\/B:APPT.0000025803.17498.26","article-title":"Chondroptosis: A variant of apoptotic cell death in chondrocytes?","volume":"9","author":"Roach","year":"2004","journal-title":"Apoptosis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1055\/s-0042-110571","article-title":"Glucocorticoid signaling and bone biology","volume":"48","author":"Komori","year":"2016","journal-title":"Horm. Metab. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/jcp.21117","article-title":"PIM-2 is an independent regulator of chondrocyte survival and autophagy in the epiphyseal growth plate","volume":"213","author":"Bohensky","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.joca.2003.10.006","article-title":"Chondrocyte death during murine osteoarthritis","volume":"12","author":"Mistry","year":"2004","journal-title":"Osteoarthr. Cartil."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.joca.2006.06.012","article-title":"Chondrocyte death by apoptosis is associated with cartilage matrix degradation","volume":"15","author":"Thomas","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/1529-0131(199809)41:9<1632::AID-ART14>3.0.CO;2-A","article-title":"Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis","volume":"41","author":"Hashimoto","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/1529-0131(199802)41:2<284::AID-ART12>3.0.CO;2-T","article-title":"Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology","volume":"41","author":"Blanco","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/art.20020","article-title":"Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and expression of caspase-3","volume":"50","author":"Sharif","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_42","first-page":"455","article-title":"Apoptotic chondrocyte death in human osteoarthritis","volume":"27","author":"Kim","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/1529-0131(199807)41:7<1266::AID-ART18>3.0.CO;2-Y","article-title":"Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis","volume":"41","author":"Hashimoto","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.joca.2004.08.003","article-title":"Characterization of mature vs. aged rabbit articular cartilage: Analysis of cell density, apoptosis-related gene expression and mechanisms controlling chondrocyte apoptosis","volume":"12","author":"Robertson","year":"2004","journal-title":"Osteoarthr. Cartil."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/(SICI)1097-0185(199804)250:4<418::AID-AR4>3.0.CO;2-T","article-title":"Chondrocyte apoptosis increases with age in the articular cartilage of adult animals","volume":"250","author":"Adams","year":"1998","journal-title":"Anat. Rec."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1002\/art.21874","article-title":"Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis","volume":"54","author":"Hermida","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.joca.2005.12.010","article-title":"Beneficial effects of intra-articular caspase inhibition therapy following osteochondral injury","volume":"14","author":"Dang","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1172\/JCI83676","article-title":"Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis","volume":"126","author":"Zhang","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11926-008-0007-8","article-title":"Cell death in osteoarthritis","volume":"10","author":"Loeser","year":"2008","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1053\/joca.2000.0417","article-title":"How severe must repetitive loading be to kill chondrocytes in articular cartilage?","volume":"9","author":"Clements","year":"2001","journal-title":"Osteoarthr. Cartil."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1053\/joca.2001.0468","article-title":"Human chondrocyte apoptosis in response to mechanical injury","volume":"9","author":"Hashimoto","year":"2001","journal-title":"Osteoarthr. Cartil."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1080\/03008200490514121","article-title":"Cyclic loading can denature type II collagen in articular cartilage","volume":"45","author":"Clements","year":"2004","journal-title":"Connect. Tissue Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1002\/art.11246","article-title":"Accelerated, aging-dependent development of osteoarthritis in \u03b11 integrin-deficient mice","volume":"48","author":"Zemmyo","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1006\/excr.1997.3692","article-title":"Apoptosis of chondrocytes in transgenic mice lacking collagen II","volume":"235","author":"Yang","year":"1997","journal-title":"Exp. Cell Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/art.34453","article-title":"Osteoarthritis: A disease of the joint as an organ","volume":"64","author":"Loeser","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1002\/art.33495","article-title":"Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4","volume":"64","author":"Schelbergen","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1002\/1529-0131(200007)43:7<1560::AID-ANR21>3.0.CO;2-S","article-title":"Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization","volume":"43","author":"Johnson","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nrrheum.2010.213","article-title":"The role of mitochondria in osteoarthritis","volume":"7","author":"Blanco","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/art.11438","article-title":"Influence of tissue maturation and antioxidants on the apoptotic response of articular cartilage after injurious compression","volume":"50","author":"Kurz","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1136\/ard.2004.022152","article-title":"Effect of nitric oxide on mitochondrial respiratory activity of human articular chondrocytes","volume":"64","author":"Maneiro","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1152\/ajpcell.00214.2005","article-title":"Chondrocyte cell death mediated by reactive oxygen species-dependent activation of pkc-betai","volume":"290","author":"DelCarlo","year":"2006","journal-title":"Am. J. Physiol. Cell physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1038\/nm.2543","article-title":"Identification of a central role for complement in osteoarthritis","volume":"17","author":"Wang","year":"2011","journal-title":"Nat. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.molimm.2004.04.007","article-title":"Cell signals transduced by complement","volume":"41","author":"Ziporen","year":"2004","journal-title":"Mol. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.joca.2014.04.025","article-title":"Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C\/EBP homologous protein","volume":"22","author":"Uehara","year":"2014","journal-title":"Osteoarthr. Cartil."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1002\/art.24864","article-title":"SIRT1 regulation of apoptosis of human chondrocytes","volume":"60","author":"Takayama","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1002\/art.27369","article-title":"SIRT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway","volume":"62","author":"Gagarina","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1136\/ard.2011.200504","article-title":"Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SIRT1 mice","volume":"71","author":"Gabay","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1210\/en.2003-0990","article-title":"Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength","volume":"145","author":"Jia","year":"2004","journal-title":"Endocrinology"},{"key":"ref_69","first-page":"719","article-title":"Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: Dissociation from transcriptional activity","volume":"104","author":"Kousteni","year":"2001","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S8756-3282(00)00309-4","article-title":"In vivo regulation of apoptosis in metaphyseal trabecular bone of young rats by synthetic human parathyroid hormone (1\u201334) fragment","volume":"27","author":"Stanislaus","year":"2000","journal-title":"Bone"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5339","DOI":"10.1210\/endo.140.11.7135","article-title":"Estrogen prevents glucocorticoid-induced apoptosis in osteoblasts in vivo and in vitro","volume":"140","author":"Gohel","year":"1999","journal-title":"Endocrinology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1172\/JCI2799","article-title":"Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone","volume":"102","author":"Weinstein","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1172\/JCI6800","article-title":"Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin","volume":"104","author":"Plotkin","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1172\/JCI6610","article-title":"Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone","volume":"104","author":"Jilka","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_75","first-page":"3128","article-title":"The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone","volume":"82","author":"Tomkinson","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/jbmr.2808","article-title":"Overexpression of BCLXL in osteoblasts inhibits osteoblast apoptosis and increases bone volume and strength","volume":"31","author":"Moriishi","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/jbmr.2007","article-title":"Dysapoptosis of osteoblasts and osteocytes increases cancellous bone formation but exaggerates cortical porosity with age","volume":"29","author":"Jilka","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1359\/jbmr.071211","article-title":"Role of Bcl2 in osteoclastogenesis and PTH anabolic actions in bone","volume":"23","author":"Yamashita","year":"2007","journal-title":"J. Bone Miner. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"36659","DOI":"10.1074\/jbc.M109.016915","article-title":"Anti-apoptotic molecule Bcl-2 regulates the differentiation, activation, and survival of both osteoblasts and osteoclasts","volume":"284","author":"Nagase","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Moriishi, T., Kawai, Y., Komori, H., Rokutanda, S., Eguchi, Y., Tsujimoto, Y., Asahina, I., and Komori, T. (2014). Bcl2 deficiency activates foxo through akt inactivation and accelerates osteoblast differentiation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086629"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Moriishi, T., Maruyama, Z., Fukuyama, R., Ito, M., Miyazaki, T., Kitaura, H., Ohnishi, H., Furuichi, T., Kawai, Y., and Masuyama, R. (2011). Overexpression of Bcl2 in osteoblasts inhibits osteoblast differentiation and induces osteocyte apoptosis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027487"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"31055","DOI":"10.1074\/jbc.M109.079962","article-title":"Foxo1, a novel regulator of osteoblast differentiation and skeletogenesis","volume":"285","author":"Teixeira","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.bone.2011.01.019","article-title":"FOXO1 modulates osteoblast differentiation","volume":"48","author":"Siqueira","year":"2011","journal-title":"Bone"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.cmet.2009.12.009","article-title":"FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice","volume":"11","author":"Ambrogini","year":"2010","journal-title":"Cell Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1016\/j.bbamcr.2011.06.002","article-title":"FoxO transcription factors; regulation by AKT and 14-3-3 proteins","volume":"1813","author":"Tzivion","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/415045a","article-title":"p53 mutant mice that display early ageing-associated phenotypes","volume":"415","author":"Tyner","year":"2002","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1083\/jcb.200508130","article-title":"Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling","volume":"172","author":"Lengner","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1359\/jbmr.2002.17.1.119","article-title":"Disruption of the p53 gene results in preserved trabecular bone mass and bone formation after mechanical unloading","volume":"17","author":"Sakai","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1136\/ard.2003.011643","article-title":"Trabecular bone mass and bone formation are preserved after limb immobilisation in p53 null mice","volume":"63","author":"Okazaki","year":"2004","journal-title":"Ann. Rheum. Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1083\/jcb.200507106","article-title":"p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling","volume":"172","author":"Wang","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/(SICI)1098-2744(199906)25:2<132::AID-MC8>3.0.CO;2-2","article-title":"p53 transactivity during in vitro osteoblast differentiation in a rat osteosarcoma cell line","volume":"25","author":"Schwartz","year":"1999","journal-title":"Mol. Carcinog."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1016\/j.bbamcr.2011.03.010","article-title":"Akt, foxO and regulation of apoptosis","volume":"1813","author":"Zhang","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Marks, S.C., and Odgren, P.R. (2002). Structure and Development of the Skeleton, Academic Press.","DOI":"10.1016\/B978-012098652-1.50103-7"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1007\/s00424-008-0591-5","article-title":"Connexins, pannexins, innexins: Novel roles of \u201chemi-channels\u201d","volume":"457","author":"Scemes","year":"2009","journal-title":"Pflugers Arch."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.bbamem.2012.01.017","article-title":"The biochemistry and function of pannexin channels","volume":"1828","author":"Penuela","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/nature09413","article-title":"Pannexin 1 channels mediate \u2032find-me\u2032 signal release and membrane permeability during apoptosis","volume":"467","author":"Chekeni","year":"2010","journal-title":"Nature"},{"key":"ref_97","first-page":"125","article-title":"ATP P2 receptors and regulation of bone effector cells","volume":"4","author":"Gallagher","year":"2004","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/S8756-3282(02)00877-3","article-title":"Adenosine triphosphate stimulates human osteoclast activity via upregulation of osteoblast-expressed receptor activator of nuclear factor-kappa B ligand","volume":"31","author":"Buckley","year":"2002","journal-title":"Bone"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"16909","DOI":"10.1074\/jbc.M410764200","article-title":"P2Y6 nucleotide receptors activate NF-\u03baB and increase survival of osteoclasts","volume":"280","author":"Korcok","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.4049\/jimmunol.1002780","article-title":"The P2X7 receptor and Pannexin-1 are both required for the promotion of multinucleated macrophages by the inflammatory cytokine GM-CSF","volume":"187","author":"Lemaire","year":"2011","journal-title":"J. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"C752","DOI":"10.1152\/ajpcell.00228.2008","article-title":"P2X7 receptor-pannexin1 complex: Pharmacology and signaling","volume":"295","author":"Iglesias","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0303-7207(99)00174-4","article-title":"Osteocyte function, osteocyte death and bone fracture resistance","volume":"159","author":"Noble","year":"2000","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1359\/jbmr.081210","article-title":"Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue","volume":"24","author":"Cardoso","year":"2009","journal-title":"J. Bone Miner. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.bone.2009.11.006","article-title":"Osteocyte apoptosis and control of bone resorption following ovariectomy in mice","volume":"46","author":"Emerton","year":"2010","journal-title":"Bone"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1359\/jbmr.2000.15.1.60","article-title":"Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo","volume":"15","author":"Verborgt","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"46","DOI":"10.22203\/eCM.v006a05","article-title":"Bone microdamage and cell apoptosis","volume":"6","author":"Noble","year":"2003","journal-title":"Eur. Cells Mater."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.cmet.2007.05.001","article-title":"Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction","volume":"5","author":"Tatsumi","year":"2007","journal-title":"Cell Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/sj.cdd.4400852","article-title":"The autophagosomal-lysosomal compartment in programmed cell death","volume":"8","author":"Bursch","year":"2001","journal-title":"Cell Death Differ."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.bone.2014.03.049","article-title":"Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo","volume":"64","author":"Kennedy","year":"2014","journal-title":"Bone"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/jbmr.2740","article-title":"Pannexin-1 and P2X7-receptor are required for apoptotic osteocytes in fatigued bone to trigger rankl production in neighboring bystander osteocytes","volume":"31","author":"Cheung","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.1376506","article-title":"Necrotic death as a cell fate","volume":"20","author":"Zong","year":"2006","journal-title":"Genes Dev."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"307","DOI":"10.4049\/jimmunol.173.1.307","article-title":"High mobility group box protein 1: An endogenous signal for dendritic cell maturation and Th1 polarization","volume":"173","author":"Messmer","year":"2004","journal-title":"J. Immunol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"7370","DOI":"10.1074\/jbc.M306793200","article-title":"Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein","volume":"279","author":"Park","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nri1594","article-title":"High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal","volume":"5","author":"Lotze","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.molimm.2013.07.008","article-title":"RAGE and TLRs: Relatives, friends or neighbours?","volume":"56","author":"Ibrahim","year":"2013","journal-title":"Mol. Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.bone.2009.08.050","article-title":"Control of RANKL gene expression","volume":"46","year":"2010","journal-title":"Bone"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/jbmr.548","article-title":"Cell autonomous requirement of connexin 43 for osteocyte survival: Consequences for endocortical resorption and periosteal bone formation","volume":"27","author":"Bivi","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/jbmr.2374","article-title":"Connexin 43 channels are essential for normal bone structure and osteocyte viability","volume":"30","author":"Xu","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/cr.2010.21","article-title":"BCL2 inhibits cell adhesion, spreading, and motility by enhancing actin polymerization","volume":"20","author":"Ke","year":"2010","journal-title":"Cell Res."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Moriishi, T., Fukuyama, R., Ito, M., Miyazaki, T., Maeno, T., Kawai, Y., Komori, H., and Komori, T. (2012). Osteocyte network; a negative regulatory system for bone mass augmented by the induction of rankl in osteoblasts and sost in osteocytes at unloading. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040143"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/nm.2448","article-title":"Matrix-embedded cells control osteoclast formation","volume":"17","author":"Xiong","year":"2011","journal-title":"Nat. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/nm.2452","article-title":"Evidence for osteocyte regulation of bone homeostasis through RANKL expression","volume":"17","author":"Nakashima","year":"2011","journal-title":"Nat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/12\/2045\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:28:05Z","timestamp":1760210885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/12\/2045"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,6]]},"references-count":122,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,12]]}},"alternative-id":["ijms17122045"],"URL":"https:\/\/doi.org\/10.3390\/ijms17122045","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,6]]}}}