Hypoxic stress enhances osteoclast differentiation via increasing IGF2 production by non-osteoclastic cells

Fukuoka, Hayato; Aoyama, Mineyoshi; Miyazawa, Ken; Asai, Kiyofumi; Goto, Shigemi

doi:10.1016/j.bbrc.2005.01.042

Cited by 43 publications

(36 citation statements)

References 38 publications

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“…6 However, small numbers of stromal cells are also present in this model system, leaving open the possibility that hypoxia is acting upon osteoblastic/fibroblastic precursor cells to increase osteoclastogenic cytokine production. 21 Using the hPBMC system, the present results indicate that the osteoclastogenic response to hypoxia is an intrinsic property of human circulating mononuclear cells that does not require cells of the osteoblast-fibroblast lineage. Despite recent reports of circulating osteoblast lineage cells in human blood 22 we were unable to detect endogenous RANKL, the key osteoclastogenic cytokine expressed by osteoblasts in these cultures; moreover, cells adherent to the ivory discs after 14 days culture stained uniformly and strongly for TRAP, a standard marker for cells of the osteoclast lineage.…”

Section: Resultsmentioning

confidence: 91%

Hypoxia stimulates osteoclast formation from human peripheral blood

Utting

Flanagan

Brandao-Burch

et al. 2010

Cell Biochemistry & Function

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Active pathological bone destruction in humans often occurs in locations where oxygen tension (pO(2)) is likely to be low, for example, at the sites of tumours, inflammation, infections and fractures, or the poorly vascularized yellow fatty marrow of the elderly. We examined the effect of pO(2) on formation of osteoclasts, the cells responsible for bone resorption, in 14-day cultures of normal human peripheral blood mononuclear cells (hPBMCs) on ivory discs. Hypoxia (1-2% O(2)) caused threefold increases in the number of osteoclasts formed, compared with 20% O(2). Hypoxia also caused a twofold increase in the number of nuclei per osteoclast, leading to stimulations of resorption pit formation of up to 10-fold. Exposure to hypoxia led to stabilization of the hypoxia-inducible factors, HIF1alpha and HIF2alpha, and upregulation of vascular endothelial growth factor and interleukin-6 expression by hPBMCs. These findings help explain why extravasation of mononuclear precursors into relatively O(2)-deficient bone microenvironments could result in osteoclast formation and suggest a new mechanism for the bone loss associated with the pathophysiological conditions where hypoxia commonly occurs.

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Section: Resultsmentioning

confidence: 91%

Hypoxia stimulates osteoclast formation from human peripheral blood

Utting

Flanagan

Brandao-Burch

et al. 2010

Cell Biochemistry & Function

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“…Hypoxia can promote cellular differentiation/lineage selection. For example, hypoxia can promote osteoclast differentiation [Arnett et al, 2003;Fukuoka et al, 2005] and mesenchymal bone marrow cell differentiation into chondrocytes [Mizuno and Glowacki, 2005;Robins et al, 2005;Schipani, 2005] and (through HIF-1 elevation) macrophage differentiation [Oda et al, 2006]. Hypoxic conditions can also suppress differentiation in cell types such as myeloid and hematopoietic cells [Sahai et al, 1994;Matsuda et al, 1998;Desplat et al, 2002;Song et al, 2002;Jiang and Mendelson, 2003] and can suppress adipogenesis and adipocyte maturation [Yun et al, 2002;Zhou et al, 2005].…”

Section: Discussionmentioning

confidence: 99%

Prolyl‐hydroxylase inhibition and HIF activation in osteoblasts promotes an adipocytic phenotype

Irwin

LaPres

Kinser

et al. 2006

J of Cellular Biochemistry

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Bone is a dynamic environment where cells sense and adapt to changes in nutrient and oxygen availability. Conditions associated with hypoxia in bone are also associated with bone loss. In vitro hypoxia (2% oxygen) alters gene expression in osteoblasts and osteocytes and induces cellular changes including the upregulation of hypoxia inducible factor (HIF) levels. Our studies show that osteoblasts respond to hypoxia (2% oxygen) by enhancing expression of genes associated with adipocyte/lipogenesis phenotype (C/EBPbeta, PPARgamma2, and aP2) and by suppressing expression of genes associated with osteoblast differentiation (alkaline phosphatase, AP). Hypoxia increased HIF protein levels, hypoxic response element (HRE) binding, and HRE-reporter activity. We also demonstrate that prolyl-hydroxylases 2 and 3 (PHD2, PHD3), one of the major factors coordinating HIF degradation under normoxic but not hypoxic conditions, are induced in osteoblasts under hypoxic conditions. To further determine the contribution of PHDs and upregulated HIF activity in modulating osteoblast phenotype, we treated osteoblasts with a PHD inhibitor, dimethyloxaloylglycine (DMOG), and maintained cells under normoxic conditions. Similar to hypoxic conditions, HRE reporter activity was increased and adipogenic gene expression was increased while osteoblastic genes were suppressed. Taken together, our findings indicate a role for PHDs and HIFs in the regulation of osteoblast phenotype.

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“…Although previous reports have shown that hypoxia induces osteoclastogenesis via direct action on osteoclast precursor cells or via indirect action on osteoblasts and bone marrow cells (Fukuoka et al, 2005;Knowles and Athanasou, 2008), there have been no reports on hypoxia-induced RANKL expression …”

Section: Hypoxia-induced Rankl Expression Is Hif-1α Dependentmentioning

confidence: 98%

“…Hypoxia stimulates bone resorption by promoting both the osteoclastic differentiation of hematopoietic precursor cells and the bone-resorbing activity of osteoclasts (Arnett et al, 2003;Knowles and Athanasou, 2009). In addition to direct regulation of osteoclast precursor cells, hypoxia enhances osteoclast differentiation indirectly by increasing the secretion of VEGF and insulin-like growth factor 2 from osteoblasts and non-osteoclastic bone marrow cells, respectively (Fukuoka et al, 2005;Knowles and Athanasou, 2008). However, the regulatory role of hypoxia in RANKL expression remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

Park

Baek

Lee

et al. 2011

Molecules and Cells

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During orthodontic tooth movement, local hypoxia and enhanced osteoclastogenesis are observed in the compression side of periodontal tissues. The receptor activator of nuclear factor-κB ligand (RANKL) is an osteoblast/ stromal cell-derived factor that is essential for osteoclastogenesis. In this study, we examined the effect of hypoxia on RANKL expression in human periodontal ligament fibroblasts (PDLFs) to investigate the relationship between local hypoxia and enhanced osteoclastogenesis in the compression side of periodontal tissues. Hypoxia significantly enhanced the levels of RANKL mRNA and protein as well as hypoxia inducible factor-1α (HIF-1α) protein in PDLFs. Constitutively active HIF-1α alone significantly increased the levels of RANKL expression in PDLFs under normoxic conditions, whereas dominant negative HIF-1α blocked hypoxia-induced RANKL expression. To investigate further whether HIF-1α directly regulates RANKL transcription, a luciferase reporter assay was performed using the reporter vector containing the RANKL promoter sequence. Exposure to hypoxia or overexpression of constitutively active HIF-1α significantly increased RANKL promoter activity, whereas dominant negative HIF-1α blocked hypoxia-induced RANKL promoter activity. Furthermore, mutations of putative HIF-1α binding elements in RANKL promoter prevented hypoxia-induced RANKL promoter activity. The results of chromatin immunoprecipitation showed that hypoxia or constitutively active HIF-1α increased the DNA binding of HIF-1α to RANKL promoter. These results suggest that HIF-1α mediates hypoxia-induced up-regulation of RANKL expression and that in compression side periodontal ligament, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in PDLFs.

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Hypoxic stress enhances osteoclast differentiation via increasing IGF2 production by non-osteoclastic cells

Cited by 43 publications

References 38 publications

Hypoxia stimulates osteoclast formation from human peripheral blood

Hypoxia stimulates osteoclast formation from human peripheral blood

Prolyl‐hydroxylase inhibition and HIF activation in osteoblasts promotes an adipocytic phenotype

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

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