BMP type I receptor inhibition reduces heterotopic ossification

Yu, Paul B.; Deng, Donna Y.; Lai, Christopher; Hong, Charles C.; Cuny, Gregory D.; Bouxsein, Mary L.; Hong, Deborah W.; McManus, Patrick M.; Katagiri, Takenobu; Sachidanandan, Chetana; Kamiya, Nobuhiro; Fukuda, T.; Mishina, Yuji; Peterson, Randall T.; Bloch, Kenneth D.

doi:10.1038/nm.1888

Cited by 562 publications

(640 citation statements)

References 34 publications

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“…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)(2)(3)(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.…”

mentioning

confidence: 99%

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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mentioning

confidence: 99%

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

Agarwal

Loder

Brownley

et al. 2015

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

Self Cite

193

223

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“…In vitro and in vivo models suggest that small-molecule inhibition of BMP type I receptors can downregulate BMP signaling, and thus may be useful in treating HO syndromes. Furthermore, heterozygous mutations in the ACVR1 gene encoding for the BMP type I receptor ALK2 have been shown to be key in the genetics of fibrodysplasia ossificans progressiva (FOP) and therefore offer potential future therapeutic targets to inhibit excess bone formation [13]. BMP-4 is involved in physiological skeletogenesis and disease such as FOP.…”

Section: Bmp Type 1 Receptor Inhibition and Bmp Antagonist Nogginmentioning

confidence: 99%

Pharmacological treatment of heterotopic ossification following hip surgery: an update

Pavlou¹,

Kyrkos²,

Tsialogiannis³

et al. 2012

Expert Opinion on Pharmacotherapy

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“…Different evidences suggested that dorsomorphin binds the ATP binding site in the kinase domain of the type I BMP receptors (ALK1, ALK2, ALK3 and ALK6) [98]. Latest studies demonstrated that dorsomorphin appears to be a poor candidate for clinical development, because it is well known that inhibits AMP activated kinase (AMPK) [160] and also exhibit significant activity on several tyrosine kinase receptors [98,161]. Nevertheless, further development of small molecule compounds with a narrower inhibition profile of BMP type I receptors is being pursued.…”

Section: Applications Of Small Molecule Bmp Inhibitors In Human Pathomentioning

confidence: 99%

“…Through a structure-activity relationship study of dorsomorphin derivatives, an optimized compound (LDN-193189, Figure 3) with higher activity and specificity on BMP type I receptors has been developed [161], although its potential effects on other protein kinases is not completely excluded [162]. In spite of their potential effects on other kinases different from the BMP pathways, these inhibitors are potentially effective for some clinical disorders.…”

Section: Applications Of Small Molecule Bmp Inhibitors In Human Pathomentioning

confidence: 99%

BMPS and Liver: More Questions than Answers

Herrera¹,

Sánchez²,

Fabregat³

2012

Current Pharmaceutical Design

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BMP type I receptor inhibition reduces heterotopic ossification

Cited by 562 publications

References 34 publications

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

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

Pharmacological treatment of heterotopic ossification following hip surgery: an update

BMPS and Liver: More Questions than Answers

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