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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

Summary of the pathological mechanisms underlying FD and potential therapeutic strategies that may be pursued.
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fig2: Summary of the pathological mechanisms underlying FD and potential therapeutic strategies that may be pursued.

Mentions: Several potential therapeutic interventions may be employed (Figure 1). A possible therapeutic strategy to be pursued in the future could be targeting the Wnt/β-catenin pathway. If the Wnt signaling pathway is halted, β-catenin will not accumulate within the cell since it is marked for ubiquitination by casein kinase 1α (CK1α), protein phosphatase 2A (PP2A) adenomatosis polyposis coli (APC), Axin, and glycogen synthase kinase 3 (GSK3) [13]. Ubiquitination of β-catenin would lead to its proteasomal degradation, thus preventing it from eliciting a cellular response contributing to FD. Therefore, if Wnt proteins can be selectively bound by ligand analogs and inactivated, the tumorigenic fibrous growth will be diminished (Figure 2).


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)

Summary of the pathological mechanisms underlying FD and potential therapeutic strategies that may be pursued.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Summary of the pathological mechanisms underlying FD and potential therapeutic strategies that may be pursued.
Mentions: Several potential therapeutic interventions may be employed (Figure 1). A possible therapeutic strategy to be pursued in the future could be targeting the Wnt/β-catenin pathway. If the Wnt signaling pathway is halted, β-catenin will not accumulate within the cell since it is marked for ubiquitination by casein kinase 1α (CK1α), protein phosphatase 2A (PP2A) adenomatosis polyposis coli (APC), Axin, and glycogen synthase kinase 3 (GSK3) [13]. Ubiquitination of β-catenin would lead to its proteasomal degradation, thus preventing it from eliciting a cellular response contributing to FD. Therefore, if Wnt proteins can be selectively bound by ligand analogs and inactivated, the tumorigenic fibrous growth will be diminished (Figure 2).

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