Distinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and function
Bone homeostasis is maintained by a balance between osteoblast-mediated bone formation and osteoclast-driven bone resorption. Hypoxia modulates this relationship partially via direct and indirect effects of the hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor on osteoclast formation an...
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| Format: | Journal article |
| Language: | English |
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Nature Research
2020
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| _version_ | 1826282830373584896 |
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| author | Knowles, H |
| author_facet | Knowles, H |
| author_sort | Knowles, H |
| collection | OXFORD |
| description | Bone homeostasis is maintained by a balance between osteoblast-mediated bone formation and osteoclast-driven bone resorption. Hypoxia modulates this relationship partially via direct and indirect effects of the hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor on osteoclast formation and bone resorption. Little data is available on the role(s) of the HIF-2α isoform of HIF in osteoclast biology. Here we describe induction of HIF-1α and HIF-2α during the differentiation of human CD14+ monocytes into osteoclasts. Knockdown of HIF-1α did not affect osteoclast differentiation but prevented the increase in bone resorption that occurs under hypoxic conditions. HIF-2α knockdown did not affect bone resorption but moderately inhibited osteoclast formation. Growth of osteoclasts in 3D gels reversed the effect of HIF-2α knockdown; HIF-2α siRNA increasing osteoclast formation in 3D. Glycolysis is the main HIF-regulated pathway that drives bone resorption. HIF knockdown only affected glucose uptake and bone resorption in hypoxic conditions. Inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) reduced osteoclast formation and activity under both basal and hypoxic conditions, emphasising the importance of glycolytic metabolism in osteoclast biology. In summary, HIF-1α and HIF-2α play different but overlapping roles in osteoclast biology, highlighting the importance of the HIF pathway as a potential therapeutic target in osteolytic disease.
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| first_indexed | 2024-03-07T00:49:45Z |
| format | Journal article |
| id | oxford-uuid:85f8ad7f-3a32-437c-bd93-a8a3e05b90a9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:49:45Z |
| publishDate | 2020 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:85f8ad7f-3a32-437c-bd93-a8a3e05b90a92022-03-26T22:01:03ZDistinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and functionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:85f8ad7f-3a32-437c-bd93-a8a3e05b90a9EnglishSymplectic ElementsNature Research2020Knowles, HBone homeostasis is maintained by a balance between osteoblast-mediated bone formation and osteoclast-driven bone resorption. Hypoxia modulates this relationship partially via direct and indirect effects of the hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor on osteoclast formation and bone resorption. Little data is available on the role(s) of the HIF-2α isoform of HIF in osteoclast biology. Here we describe induction of HIF-1α and HIF-2α during the differentiation of human CD14+ monocytes into osteoclasts. Knockdown of HIF-1α did not affect osteoclast differentiation but prevented the increase in bone resorption that occurs under hypoxic conditions. HIF-2α knockdown did not affect bone resorption but moderately inhibited osteoclast formation. Growth of osteoclasts in 3D gels reversed the effect of HIF-2α knockdown; HIF-2α siRNA increasing osteoclast formation in 3D. Glycolysis is the main HIF-regulated pathway that drives bone resorption. HIF knockdown only affected glucose uptake and bone resorption in hypoxic conditions. Inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) reduced osteoclast formation and activity under both basal and hypoxic conditions, emphasising the importance of glycolytic metabolism in osteoclast biology. In summary, HIF-1α and HIF-2α play different but overlapping roles in osteoclast biology, highlighting the importance of the HIF pathway as a potential therapeutic target in osteolytic disease. |
| spellingShingle | Knowles, H Distinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and function |
| title | Distinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and function |
| title_full | Distinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and function |
| title_fullStr | Distinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and function |
| title_full_unstemmed | Distinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and function |
| title_short | Distinct roles for the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in human osteoclast formation and function |
| title_sort | distinct roles for the hypoxia inducible transcription factors hif 1alpha and hif 2alpha in human osteoclast formation and function |
| work_keys_str_mv | AT knowlesh distinctrolesforthehypoxiainducibletranscriptionfactorshif1alphaandhif2alphainhumanosteoclastformationandfunction |