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Apoptotic chondrocytes were detected by <jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content> assay. Ultrastructural changes were examined by transmission electron microscope (<jats:styled-content style=\"fixed-case\">TEM<\/jats:styled-content>). Biochemical markers associated with apoptosis (eg, caspase\u20103) and necroptosis (eg, <jats:styled-content style=\"fixed-case\">RIP<\/jats:styled-content>3) were investigated by immunohistochemistry. In <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> cartilage chondrocyte death was characterized by paler staining of the cells. Multiple chondral cell clusters surrounded the areas lacking cells in the deep zone. The per cent of <jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content>\u2010positive and <jats:styled-content style=\"fixed-case\">RIP<\/jats:styled-content>3\u2010positive chondrocytes were higher in the middle zones of <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> samples; however, there was some positive staining for <jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content> but negative staining for caspase\u20103. Immunohistochemistry failed to detect significant differences in caspase\u20103 levels in <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> children compared to controls, suggesting that beside apoptosis necroptosis dominates as a cell death mechanism in the middle zone of cartilage from <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> children. To clarify further the presence of chondrocyte necroptosis in <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content>, we performed <jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content>, caspase\u20103 and <jats:styled-content style=\"fixed-case\">RIP<\/jats:styled-content>3 staining in a rat <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> model which is based upon T\u20102 toxin treatment under selenium\u2010deficient conditions. Apoptosis and necroptosis co\u2010existed in the middle zone in this rat <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> model. Ultrastructural analysis of chondrocyte from deep cartilage revealed abnormal cells with numerous morphological changes, such as plasma membrane breakdown, generalized swelling of the cytoplasm and loss of identifiable organelles. Chondrocyte death by necrosis in the deep zone of cartilages in <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> may be a result of exposure to T\u20102 toxin from bone marrow or bloodstream under selenium\u2010deficient nutrition status in <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> endemic areas. Chondrocyte death plays a key role in either the initiation or the progression of <jats:styled-content style=\"fixed-case\">KBD<\/jats:styled-content> pathogenesis.<\/jats:p>","DOI":"10.1111\/iep.12297","type":"journal-article","created":{"date-parts":[[2019,1,25]],"date-time":"2019-01-25T05:54:30Z","timestamp":1548395670000},"page":"312-322","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Death of chondrocytes in Kashin\u2010Beck disease: Apoptosis, necrosis or necroptosis?"],"prefix":"10.1111","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5885-0214","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Public Health, Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission, Xi'an Jiaotong University Xi'an, 710061  Shaanxi People's Republic of 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 Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission, Xi'an Jiaotong University Xi'an, 710061  Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Public Health, Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission, Xi'an Jiaotong University Xi'an, 710061  Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyou","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Public Health, Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission, 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