HIF-1α induces hypoxic apoptosis of MLO-Y4 osteocytes via JNK/caspase-3 pathway and the apoptotic-osteocyte-mediated osteoclastogenesis in vitro

Tissue Cell. 2020 Dec:67:101402. doi: 10.1016/j.tice.2020.101402. Epub 2020 Jun 29.


Apoptotic osteocytes were found in the hypoxic bone microenvironment in osteoporosis, osteotomy, orthodontic tooth movement and periodontitis, and played a key role in bone remolding and the differentiation of osteoclasts. Hypoxia inducible factor-1α(HIF-1α), as a transcription factor under hypoxic conditions, has been confirmed to participate in cell apoptosis. However, the effect of HIF-1α on osteocytes apoptosis and the osteocyte-mediated osteoclast formation remains elusive. Here, we hypothesized that HIF-1α was involved in osteocytes apoptosis. Our results showed that CoCl2 increased the MLO-Y4 cells apoptosis by upregulating the proapoptotic gene expression of caspase-3. Moreover, siRNA-mediated knockdown of HIF-1α decreased the phosphorylation by JNK and the activation of caspase-3 to inhibit the cell apoptosis in MLO-Y4. Furthermore, SP600125, an inhibitor of JNK, reversed CoCl2-induced the increased apoptosis of MLO-Y4 cells in term of reducing the expression of caspase-3. These findings revealed that HIF-1α served as a pro-apoptotic factor in the apoptosis of MLO-Y4 cells cultured with CoCl2, by activating the JNK/caspase-3 signaling pathway. Besides, the osteocyte-mediated osteoclastogenesis was reduced with the decline of the expression of HIF-1α and caspase-3 in MLO-Y4 cells. Our study provided an idea for a more comprehensive understanding of HIF-1α and the process of bone remodeling.

Keywords: HIF-1α; Hypoxia; JNK; Osteoclastogenesis; Osteocyte apoptosis; caspase-3.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Caspase 3 / metabolism*
  • Cell Differentiation / drug effects
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / genetics
  • Cell Line
  • Cobalt / pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • MAP Kinase Signaling System* / drug effects
  • Mice
  • Osteocytes / drug effects
  • Osteocytes / metabolism*
  • Osteogenesis* / drug effects
  • Osteogenesis* / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • RNA, Small Interfering
  • Cobalt
  • Caspase 3
  • cobaltous chloride