Abstract
Hypoxia-inducible factors (HIFs) have become key transcriptional regulators of metabolism, angiogenesis, erythropoiesis, proliferation, inflammation and metastases. HIFs are tightly regulated by the tissue microenvironment. Under the influence of the hypoxic milieu, HIF proteins allow the tissue to adapt its response. This is especially critical for bone, as it constitutes a highly hypoxic environment. As such, bone structure and turnover are strongly influenced by the modulation of oxygen availability and HIFs. Both, bone forming osteoblasts and bone resorbing osteoclasts are targeted by HIFs and modulators of oxygen tension. Experimental and clinical data have delineated the importance of HIF responses in different osteoclast-mediated pathologies. This review will focus on the influence of HIF expression on the regulation of osteoclasts in homeostasis as well as during inflammatory and malignant bone diseases.
Highlights
Bone is a highly dynamic tissue that undergoes constant remodeling to adapt to changing functional and metabolic demands, and to repair microdamages that naturally occur throughout life
The hydroxylation reaction is inhibited under hypoxic condition, HIFα subunits are stabilized and translocate to the nucleus, where they heterodimerize with HIF1β and bind to HRE located within regulatory elements of Hypoxia-inducible factors (HIFs) target genes (Dengler et al, 2014)
These are involved in multiple processes such as angiogenesis (Vegf, Pdgf, and Fgf2), erythropoiesis (Epo, Tfr1, and Cp), metabolism (Glut1, Pdk1, Hk2, Ldha, and Mct4), proliferation (Tnfa, Ccnd1, and Igf2), inflammation (Il1b, Il6, and Il17) and metastasis (Met1, Lox1) (Flamme et al, 1997; Jaakkola et al, 2001; Mahon et al, 2001; Wenger et al, 2005; Semenza, 2014)
Summary
Bone is a highly dynamic tissue that undergoes constant remodeling to adapt to changing functional and metabolic demands, and to repair microdamages that naturally occur throughout life. The hydroxylation reaction is inhibited under hypoxic condition, HIFα subunits are stabilized and translocate to the nucleus, where they heterodimerize with HIF1β and bind to HRE located within regulatory elements of HIF target genes (Dengler et al, 2014) These are involved in multiple processes such as angiogenesis (Vegf, Pdgf, and Fgf2), erythropoiesis (Epo, Tfr, and Cp), metabolism (Glut, Pdk, Hk2, Ldha, and Mct4), proliferation (Tnfa, Ccnd, and Igf2), inflammation (Il1b, Il6, and Il17) and metastasis (Met, Lox1) (Flamme et al, 1997; Jaakkola et al, 2001; Mahon et al, 2001; Wenger et al, 2005; Semenza, 2014). Given the pertinent role of osteoclasts in bone homeostasis and bone disease, and their regulation via hypoxia signaling, this review will summarize the current knowledge on the role of hypoxia signaling on osteoclasts and its potential as therapeutic target to inhibit osteoclast function in inflammatory and malignant bone diseases
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