Hypoxia, hypoxia-inducible factor (HIF) and bone homeostasis: focus on osteoclast-mediated bone resorption (original) (raw)
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The Journal of pathology, 2017
Osteogenic-angiogenic coupling is promoted by the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, provoking interest in HIF activation as a therapeutic strategy to improve osteoblast mineralization and treat pathological osteolysis. However, HIF also enhances the bone-resorbing activity of mature osteoclasts. It is therefore essential to determine the full effect(s) of HIF on both the formation and the bone-resorbing function of osteoclasts in order to understand how they might respond to such a strategy. Expression of HIF-1α mRNA and protein increased during osteoclast differentiation from CD14+ monocytic precursors, additionally inducing expression of the HIF-regulated glycolytic enzymes. However, HIF-1α siRNA only moderately affected osteoclast differentiation, accelerating fusion of precursor cells. HIF induction by inhibition of the regulatory prolyl-4-hydroxylase (PHD) enzymes reduced osteoclastogenesis, but was confirmed to enhance bone resorption by mature os...
Scientific Reports
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...
HIF targets in bone remodeling and metastatic disease
The bone marrow is a hypoxic microenvironment that is rich in growth factors and blood vessels and is readily colonized by tumor cells disseminated from numerous cancers including tumors of the breast, prostate, lung, and skin. The origin of metastatic growth promoting factors for tumor cells disseminated to the bone marrow is derived from multiple sources: the bone matrix, which is a reservoir for growth factors, and cells residing in the marrow and along bone surfaces, such as osteoblasts, osteoclasts, macrophages, and T cells, which secrete cytokines and chemokines. Low oxygen levels within the bone marrow induce hypoxia signaling pathways such as hypoxia inducible factor (HIF), which is regulated by oxygen requiring prolyl hydroxylases (PHDs) and von Hippel-Lindau (VHL) tumor suppressor. These hypoxia signaling pathways have profound effects on bone development and homeostasis. Likewise, hypoxic conditions observed in local breast and prostate tumors point to a role for hypoxia-inducible genes in metastasis to and colonization of the bone marrow. This review will explore the role of hypoxia-regulated factors in bone development and remodeling, and how these elements may contribute to solid tumor metastasis to the bone.
Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration
Proceedings of the …, 2008
The hypoxia-inducible factor-1␣ (HIF-1␣) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1␣ pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1␣ activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1␣ in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro. One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1␣ pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing.
Hypoxia signalling manipulation for bone regeneration
Expert reviews in molecular medicine, 2015
Hypoxia-inducible factor (HIF) signalling is intricately involved in coupling angiogenesis and osteogenesis during bone development and repair. Activation of HIFs in response to a hypoxic bone micro-environment stimulates the transcription of multiple genes with effects on angiogenesis, precursor cell recruitment and differentiation. Substantial progress has been made in our understanding of the molecular mechanisms by which oxygen content regulates the levels and activity of HIFs. In particular, the discovery of the role of oxygen-dependent hydroxylase enzymes in modulating the activity of HIF-1α has sparked interest in potentially promising therapeutic strategies in multiple clinical fields and most recently bone healing. Several small molecules, termed hypoxia mimics, have been identified as activators of the HIF pathway and have demonstrated augmentation of both bone vascularity and bone regeneration in vivo. In this review we discuss key elements of the hypoxic signalling pathw...
Activation of the hypoxia-inducible factor-1 pathway accelerates bone regeneration
Proceedings of the National Academy of Sciences, 2008
The hypoxia-inducible factor-1␣ (HIF-1␣) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1␣ pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1␣ activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1␣ in osteoblasts had impaired angiogenesis and bone healing.
Leukemia, 2013
Hypoxia-inducible transcription factor-1 (HIF-1a) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1a inhibition by a lentivirus short hairpin RNA pool on MM cell growth either in vitro or in vivo and on the transcriptional and pro-angiogenic profiles of MM cells. HIF-1a suppression did not have a significant impact on MM cell proliferation and survival in vitro although, increased the antiproliferative effect of lenalidomide. On the other hand, we found that HIF-1a inhibition in MM cells downregulates the pro-angiogenic genes VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1a. The effect of HIF-1a inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1a inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1a inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1a suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1a as a potential therapeutic target in MM.