px-478 and Wounds-and-Injuries

px-478 has been researched along with Wounds-and-Injuries* in 1 studies

Other Studies

1 other study(ies) available for px-478 and Wounds-and-Injuries

Article	Year
Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification. Proceedings of the National Academy of Sciences of the United States of America, 2016, Jan-19, Volume: 113, Issue:3 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. Topics: Activin Receptors, Type I; Adipose Tissue; Animals; Burns; Chondrogenesis; Disease Models, Animal; Gene Regulatory Networks; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Integrases; Luminescent Measurements; Mesenchymal Stem Cells; Mice, Knockout; Models, Biological; Mustard Compounds; Ossification, Heterotopic; Phenylpropionates; Receptor, Platelet-Derived Growth Factor alpha; RNA, Messenger; Signal Transduction; Sirolimus; SOX9 Transcription Factor; Tendons; Tenotomy; Up-Regulation; Wound Healing; Wounds and Injuries; X-Ray Microtomography	2016

Article

Year

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

Proceedings of the National Academy of Sciences of the United States of America, 2016, Jan-19, Volume: 113, Issue:3

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.

Topics: Activin Receptors, Type I; Adipose Tissue; Animals; Burns; Chondrogenesis; Disease Models, Animal; Gene Regulatory Networks; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Integrases; Luminescent Measurements; Mesenchymal Stem Cells; Mice, Knockout; Models, Biological; Mustard Compounds; Ossification, Heterotopic; Phenylpropionates; Receptor, Platelet-Derived Growth Factor alpha; RNA, Messenger; Signal Transduction; Sirolimus; SOX9 Transcription Factor; Tendons; Tenotomy; Up-Regulation; Wound Healing; Wounds and Injuries; X-Ray Microtomography

2016