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Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders.

Faruqi T, Dhawan N, Bahl J, Gupta V, Vohra S, Tu K, Abdelmagid SM - Biomed Res Int (2014)

Bottom Line: Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP.Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed.There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

View Article: PubMed Central - PubMed

Affiliation: Nova Southeastern University Health Sciences Division, Fort-Lauderdale-Davie, FL 33314, USA.

ABSTRACT
A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

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Related in: MedlinePlus

Schematic diagram of the pathogenesis of FOB: mutation of the Alk2 subunit (blue arrow) of BMP receptor I leads to constitutive phosphorylation of the downstream regulated-smad1, -5, and -8 that associate with smad4. Multimeric smad complex translocates to the nucleus and positively regulates several transcription factors responsible for osteoblast differentiation and bone formation.
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fig5: Schematic diagram of the pathogenesis of FOB: mutation of the Alk2 subunit (blue arrow) of BMP receptor I leads to constitutive phosphorylation of the downstream regulated-smad1, -5, and -8 that associate with smad4. Multimeric smad complex translocates to the nucleus and positively regulates several transcription factors responsible for osteoblast differentiation and bone formation.

Mentions: There is no current cure for FOP. The current management of FOP is early diagnosis, preventing iatrogenic trauma, and alleviating pain during episodic flare-ups. Several studies have indicated that FOP is associated with the bone morphogenetic protein (BMP) signaling pathway. BMPs are responsible for the stimulation of bone formation through binding to the activin receptor type 1 (encoded by the AVCR1 gene receptor), a BMP type 1 receptor. Thus, in 2006 Kaplan et al. [26] identified a mutation in activin receptor IA/activin-like kinase 2 (AVCR1/ALK2) in all patients presenting with FOP (Figure 5). DNA sequencing displayed the occurrence of missense mutation in the glycine-serine activation domain in individuals with FOP. Not all FOP cases are caused by the common mutation, as there are several FOP variants with varying phenotypes. Importantly, Chakkalakal et al. [32] further elucidated the mechanism of FOP using a FOP knock-in mouse model. Thus, FOP results from a mutation in the gene ACVR1/ALK2, which causes the amino acid histidine to be substituted in place of arginine at the 206 codon. Due to the discovery of this highly specific mutation in the FOP gene, therapeutic modalities can now be aimed at blocking the AVCR1/ALK2 pathway. Thus, the identification of factors that are a part of or that aid the BMP signaling pathway has been the focus of recent studies. Mao et al. suggested the potential role of matrix metalloproteinase-10 (MMP-10) in the HO of muscle in FOP patients. They showed that MMP-10 stimulated myoblast differentiation into osteoblasts through the interactions with BMP pathway [33]. Thus, MMP-10 may serve as a potential therapeutic target. Giacopelli et al. [34] recently reported a significant finding that transcription factors including Egr-1, Egr-2, ZBTB7A/LRF, Hey1, and Sp1 are responsible for the regulation of the ACVR1 promoter through binding to the −762/−308 region. Furthermore, additional studies have shown that miR-148a may be a critical mediatory agent of ACVR1 [35, 36]. Thus, disruption of the pathway through blocking or slowing down any of these transcription factors presents the most promising form of potential therapy to date.


Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders.

Faruqi T, Dhawan N, Bahl J, Gupta V, Vohra S, Tu K, Abdelmagid SM - Biomed Res Int (2014)

Schematic diagram of the pathogenesis of FOB: mutation of the Alk2 subunit (blue arrow) of BMP receptor I leads to constitutive phosphorylation of the downstream regulated-smad1, -5, and -8 that associate with smad4. Multimeric smad complex translocates to the nucleus and positively regulates several transcription factors responsible for osteoblast differentiation and bone formation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230237&req=5

fig5: Schematic diagram of the pathogenesis of FOB: mutation of the Alk2 subunit (blue arrow) of BMP receptor I leads to constitutive phosphorylation of the downstream regulated-smad1, -5, and -8 that associate with smad4. Multimeric smad complex translocates to the nucleus and positively regulates several transcription factors responsible for osteoblast differentiation and bone formation.
Mentions: There is no current cure for FOP. The current management of FOP is early diagnosis, preventing iatrogenic trauma, and alleviating pain during episodic flare-ups. Several studies have indicated that FOP is associated with the bone morphogenetic protein (BMP) signaling pathway. BMPs are responsible for the stimulation of bone formation through binding to the activin receptor type 1 (encoded by the AVCR1 gene receptor), a BMP type 1 receptor. Thus, in 2006 Kaplan et al. [26] identified a mutation in activin receptor IA/activin-like kinase 2 (AVCR1/ALK2) in all patients presenting with FOP (Figure 5). DNA sequencing displayed the occurrence of missense mutation in the glycine-serine activation domain in individuals with FOP. Not all FOP cases are caused by the common mutation, as there are several FOP variants with varying phenotypes. Importantly, Chakkalakal et al. [32] further elucidated the mechanism of FOP using a FOP knock-in mouse model. Thus, FOP results from a mutation in the gene ACVR1/ALK2, which causes the amino acid histidine to be substituted in place of arginine at the 206 codon. Due to the discovery of this highly specific mutation in the FOP gene, therapeutic modalities can now be aimed at blocking the AVCR1/ALK2 pathway. Thus, the identification of factors that are a part of or that aid the BMP signaling pathway has been the focus of recent studies. Mao et al. suggested the potential role of matrix metalloproteinase-10 (MMP-10) in the HO of muscle in FOP patients. They showed that MMP-10 stimulated myoblast differentiation into osteoblasts through the interactions with BMP pathway [33]. Thus, MMP-10 may serve as a potential therapeutic target. Giacopelli et al. [34] recently reported a significant finding that transcription factors including Egr-1, Egr-2, ZBTB7A/LRF, Hey1, and Sp1 are responsible for the regulation of the ACVR1 promoter through binding to the −762/−308 region. Furthermore, additional studies have shown that miR-148a may be a critical mediatory agent of ACVR1 [35, 36]. Thus, disruption of the pathway through blocking or slowing down any of these transcription factors presents the most promising form of potential therapy to date.

Bottom Line: Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP.Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed.There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

View Article: PubMed Central - PubMed

Affiliation: Nova Southeastern University Health Sciences Division, Fort-Lauderdale-Davie, FL 33314, USA.

ABSTRACT
A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

Show MeSH
Related in: MedlinePlus