Hypoxia Modulates the Phenotype of Osteoblasts Isolated From Knee Osteoarthritis Patients, Leading to Undermineralized Bone Nodule Formation

Chang, Joan; Jackson, Sonya; Wardale, John; Jones, Simon W.

doi:10.1002/art.38403

Cited by 31 publications

(29 citation statements)

References 42 publications

(59 reference statements)

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“…In Tg6 mice, the increase in EPO levels is similar to the stimulation of EPO at high altitude (45). This model is also relevant for the pathophysiologic increase of endogenous EPO levels observed after bleeding/repeated phlebotomies without the confounding direct effect of hypoxia on bone cells (46) and in cases of paraneoplastic production of EPO (47), thalassemia, and polycythemia vera (48). On the other hand, the 30U‐inj model is relevant for therapeutic administration of exogenous EPO (16, 18).…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin directly stimulates osteoclast precursors and induces bone loss

et al. 2015

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Erythropoietin (EPO) primarily regulates red blood cell formation, and EPO serum levels are increased on hypoxic stress (e.g., anemia and altitude). In addition to anemia, recent discoveries suggest new therapeutic indications for EPO, unrelated to erythropoiesis. We investigated the skeletal role of EPO using several models of overexpression (Tg6 mice) and EPO administration (intermittent/continuous, high/low doses) in adult C57Bl6 female mice. Using microcomputed tomography, histology, and serum markers, we found that EPO induced a 32%-61% trabecular bone loss caused by increased bone resorption (+60%-88% osteoclast number) and reduced bone formation rate (-19 to -74%; P < 0.05 throughout). EPO targeted the monocytic lineage by increasing the number of bone monocytes/macrophages, preosteoclasts, and mature osteoclasts. In contrast to the attenuated bone formation in vivo, EPO treatment in vitro did not inhibit osteoblast differentiation and activity, suggesting an indirect effect of EPO on osteoblasts. However, EPO had a direct effect on preosteoclasts by stimulating osteoclastogenesis in isolated cultures (+60%) via the Jak2 and PI3K pathways. In summary, our findings demonstrate that EPO negatively regulates bone mass and thus bears significant clinical implications for the potential management of patients with endogenously or therapeutically elevated EPO levels.

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Section: Discussionmentioning

confidence: 99%

Erythropoietin directly stimulates osteoclast precursors and induces bone loss

et al. 2015

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“…These data suggest that hypoxic regulation of Angptl4 expression in osteoblasts is mediated by the HIF1a pathway. Angptl4 has previously been shown to be HIF1a regulated in cardiomyocytes, adipocytes, endothelial cells, osteoblasts, and osteoclasts . In a study of human osteoblasts isolated from the knee of osteoarthritic patients, Angptl4 mRNA expression increased under hypoxic conditions (2% O 2 ) and in cells treated with the hypoxia mimetic dimethyl‐oxalylglycine (DMOG) …”

Section: Discussionmentioning

confidence: 99%

“…Its effect on angiogenesis and vascular permeability seems to be dependent on the method and form of the protein used, with both proangiogenic and antiangiogenic effects shown . Angptl4 has been shown to be upregulated during hypoxia in articular chondrocytes, osteoclasts, osteoblasts, cardiomyocytes, adipocytes, endothelial cells, and brain tissue . Of those cell types where Angptl4 expression was elevated by hypoxia, it was also shown to be HIF regulated in cardiomyocytes, adipocytes, endothelial cells, osteoblasts, and osteoclasts .…”

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confidence: 99%

“…Angptl4 has been shown to be upregulated during hypoxia in articular chondrocytes, osteoclasts, osteoblasts, cardiomyocytes, adipocytes, endothelial cells, and brain tissue . Of those cell types where Angptl4 expression was elevated by hypoxia, it was also shown to be HIF regulated in cardiomyocytes, adipocytes, endothelial cells, osteoblasts, and osteoclasts . Additionally, Angptl4 has been shown to be upregulated in epithelial tumor lines is an indicator of metastatic potential in breast cancer, is critical for normal re‐epithelialization and stimulates keratinocyte migration across denuded epithelium …”

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Expression of angiopoietin‐like protein 4 at the fracture site: Regulation by hypoxia and osteoblastic differentiation

Wilson

Wong

Toupadakis

et al. 2015

Journal Orthopaedic Research

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Vascular disruption that occurs as a consequence of bone fracture, leads to hypoxia at the site of damage. Hypoxia regulates the expression of a number of genes that can modulate energy conservation, cell survival, tissue regeneration and angiogenesis. In this study we investigated the expression of Angiopoietin-like 4, an adipocytokine that has additional roles in angiogenesis, at the fracture site. We demonstrate that Angptl4 mRNA expression increased early during fracture healing (day 3) returning close to baseline at day14. In the callus, Angptl4 mRNA was visualized in areas of condensing mesenchymal cells, callus cartilage and was especially high in mineralizing osteoblasts located in areas of new bone formation. In vitro, Angptl4 mRNA expression in osteoblasts increased under hypoxic conditions and in cells treated with the hypoxia mimetic desferrioxamine. Angptl4 levels were strongly induced at day 14 in differentiating MC3T3-E1 osteoblastic cells. Exogenous ANGPTL4 increased expression of Runx2, Spp1, vegfa, and Alp mRNA in differentiating osteoblasts. We suggest that the distribution of Angptl4 in the callus may be driven by hypoxia and that Angptl4 may play a role in osteoblastic differentiation, and possibly angiogenesis via regulation of VEGF. Keywords: osteoblast; hypoxia; fracture; angiopoietin-like 4; osteogenesis Subsequent to fracture, bone's vascular supply is disrupted, leading to a hypoxic environment within the developing callus. [1][2][3][4] Hypoxia is known to upregulate a subset of genes mediated by the hypoxiainducible factor (HIF) transcription pathway.5 Such genes are known to play key roles in energy conservation, cell survival and angiogenesis among others. 5,6 HIF is a heterodimer whose alpha subunit is directly regulated by oxygen tension. Under normoxic conditions HIFa is hydroxylated by prolyl hydroxylasedomain proteins (PHDs) and degraded by von HippelLindau tumor suppressor protein.7-9 However, under hypoxic conditions the activity of PHDs is reduced and HIFa levels stabilize leading to heterodimer formation with HIFb. Nuclear translocation of HIF allows binding to hypoxia responsive elements and induces transcription of target genes.10 VEGFa, a HIF1 target gene, has been extensively studied and is thought to play a role in angiogenesis and revascularization of the fracture site.3 However, there is limited data regarding a role for other angiogenic factors.Angiopoietin-like protein 4 (Angptl4) is a member of the angiopoietin/ angiopoietin-like family of proteins. While Angptl4 is commonly described as an adipocytokine involved in energy homeostasis and food intake regulation, via inhibition of lipoprotein lipase, 11-14 it has also been shown to have a role in angiogenesis. [15][16][17][18] Its effect on angiogenesis and vascular permeability seems to be dependent on the method and form of the protein used, with both proangiogenic and antiangiogenic effects shown. [15][16][17][18] Angptl4 has been shown to be upregulated during hypoxia in articular chondrocytes, osteoc...

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“…Hypoxia also increases the osteoblast production of PGE2, cyclooxygenase 2, angiopoietin‐like 4, type II collagen α1 chain, and insulin‐like growth factor binding protein 1. Moreover, an in vitro study, by using culture of primary osteoblasts isolated from knee bone from patients affected by osteoarthritis, has demonstrated that hypoxia modifies osteoblast phenotype, including the expression of genes that regulate bone matrix, bone remodeling, and bone vasculature (Chang, Jackson, Wardale, & Jones, ).…”

Section: Introductionmentioning

confidence: 99%

Osteoblast role in osteoarthritis pathogenesis

Maruotti

Corrado

Cantatore

2017

Journal Cellular Physiology

116

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Even if osteoarthritis pathogenesis is still poorly understood, numerous evidences suggest that osteoblasts dysregulation plays a key role in osteoarthritis pathogenesis. An abnormal expression of OPG and RANKL has been described in osteoarthritis osteoblasts, which is responsible for abnormal bone remodeling and decreased mineralization. Alterations in genes expression are involved in dysregulation of osteoblast function, bone remodeling, and mineralization, leading to osteoarthritis development. Moreover, osteoblasts produce numerous transcription factors, growth factors, and other proteic molecules which are involved in osteoarthritis pathogenesis.

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Hypoxia Modulates the Phenotype of Osteoblasts Isolated From Knee Osteoarthritis Patients, Leading to Undermineralized Bone Nodule Formation

Cited by 31 publications

References 42 publications

Erythropoietin directly stimulates osteoclast precursors and induces bone loss

Erythropoietin directly stimulates osteoclast precursors and induces bone loss

Expression of angiopoietin‐like protein 4 at the fracture site: Regulation by hypoxia and osteoblastic differentiation

Osteoblast role in osteoarthritis pathogenesis

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