Hif-1α regulates differentiation of limb bud mesenchyme and joint development

Provot, Sylvain; Zinyk, Dawn; Güneş, Yasemin; Kathri, Richa; Le, Quynh Thu; Kronenberg, Henry M.; Johnson, Randall S.; Longaker, Michael T.; Giaccia, Amato J.; Schipani, Ernestina

doi:10.1083/jcb.200612023

Cited by 185 publications

(238 citation statements)

References 65 publications

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“…Numerous studies have demonstrated that hypoxia induces chondrogenesis of mesenchymal cells, suggesting a prominent role for Hif1α. Additional data indicate that conditional loss of Hif1α within mesenchymal cells delays mesenchymal cell differentiation into chondrocytes (7).…”

Section: Discussionmentioning

confidence: 99%

“…These findings pave the way for pharmacologic inhibitors of hypoxia inducible factor-1α as therapeutic options for heterotopic ossification. Hypoxia inducible factor-1α (Hif1α) is one particular signaling mediator that has been shown to be critical for normal chondrogenesis (7)(8)(9)(10). Conditional Hif1α knockout mice have demonstrated that Hif1α is critical for chondrocyte survival and differentiation.…”

Section: Significancementioning

confidence: 99%

“…These mice have been shown to exhibit defective normal cartilage development (7). However, the impact on pathologic heterotopic ossification has not been demonstrated; therefore, burn/tenotomy was performed in Prx-cre/ Hif1α fl/fl mice.…”

Section: Genetic Loss Of In Mesenchymal Progenitors Prevents Formatiomentioning

confidence: 99%

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Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Agarwal

Loder

Brownley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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193

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Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1α fl:fl ) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone.is the pathologic formation of extraskeletal bone in soft tissues. This process occurs in two separate patient populations: those with severe trauma, including large surface-area burns, musculoskeletal injury, orthopedic operations, and even spinal cord injury; and those with a genetic disease known as fibrodysplasia ossificans progressiva (FOP) (1-4). FOP is caused by a hyperactivating mutation in the type I bone morphogenetic protein (BMP) receptor ACVR1 (Activin type 1 receptor), and patients with FOP develop ectopic bone lesions in the absence of any substantial trauma. The clinical sequela of these pathologic ectopic bone formations, whether in the setting of trauma or genetic mutations, include nonhealing wounds, chronic pain, and joint immobility. In the case of FOP, progressive ossification may lead to death as a result of loss of thoracic cage compliance.Treatment options for HO are limited because bone often recurs following surgical resection, and some patients may have nonresectable HO because of its sensitive location. The risk of an operation may outweigh the benefits of excision, especially in the face of recurrence (5). Therefore, there is a need to identify therapeutic options ...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Agarwal

Loder

Brownley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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193

223

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“…It has been postulated that physiological O 2 gradients in the cartilaginous growth plate have a role in modulating chondrocyte proliferation, differentiation, and growth arrest via HIF activity [REF 44]. HIF-1α is also critical for earlier steps in bone formation, such as the generation of cartilaginous primordial limb bud mesenchyme and chondrogenesis 45 .…”

Section: O 2 and Bone Morphogenesismentioning

confidence: 99%

The role of oxygen availability in embryonic development and stem cell function

Simon¹,

Keith²

2008

Nat Rev Mol Cell Biol

839

770

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Low levels of oxygen (O 2 ) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several hypoxia-inducible factors (and other molecules that mediate O 2 homeostasis), which then coordinate the development of the blood, vasculature, placenta, nervous system, and other organs. Furthermore, embryonic stem and progenitor cells frequently occupy hypoxic 'niches' and low O 2 regulates their differentiation. Recent work has revealed an important link between factors involved in regulating stem/progenitor cell behaviour and hypoxiainducible factors, which provides a molecular framework for hypoxic control of differentiation and cell fate. These findings have important implications for the development of therapies for tissue regeneration and disease.

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“…For instance, the growth plate is an avascular tissue and upon size expansion, the centrally localized chondrocytes need HIF signalling to adapt to and survive in the developing low-oxygen environment (Provot et al, 2007;Schipani et al, 2001). However, the HIF null mouse phenotype is only partially rescued by VEGF overexpression and the associated increase in angiogenesis, suggesting that other unidentified mechanisms are involved (Maes et al, 2012;Schipani et al, 2001).…”

Section: Hypoxia In Bone Repairmentioning

confidence: 99%

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

Stiers

Gastel

Carmeliet

2016

Molecular and Cellular Endocrinology

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a b s t r a c tBone tissue engineering is a promising therapeutic alternative for bone grafting of large skeletal defects. It generally comprises an ex vivo engineered combination of a carrier structure, stem/progenitor cells and growth factors. However, the success of these regenerative implants largely depends on how well implanted cells will adapt to the hostile and hypoxic host environment they encounter after implantation. In this review, we will discuss how hypoxia signalling may be used to improve bone regeneration in a tissue-engineered construct. First, hypoxia signalling induces angiogenesis which increases the survival of the implanted cells as well as stimulates bone formation. Second, hypoxia signalling has also angiogenesis-independent effects on mesenchymal cells in vitro, offering exciting new possibilities to improve tissue-engineered bone regeneration in vivo. In addition, studies in other fields have shown that benefits of modulating hypoxia signalling include enhanced cell survival, proliferation and differentiation, culminating in a more potent regenerative implant. Finally, the stimulation of endochondral bone formation as a physiological pathway to circumvent the harmful effects of hypoxia will be briefly touched upon. Thus, angiogenic dependent and independent processes may counteract the deleterious hypoxic effects and we will discuss several therapeutic strategies that may be combined to withstand the hypoxia upon implantation and improve bone regeneration.

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Hif-1α regulates differentiation of limb bud mesenchyme and joint development

Cited by 185 publications

References 65 publications

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

The role of oxygen availability in embryonic development and stem cell function

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

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