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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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Achondroplasia pathogenesis and potential therapeutic interventions.
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fig13: Achondroplasia pathogenesis and potential therapeutic interventions.

Mentions: Treatment. A number of therapeutic approaches have been attempted to reduce excessive activation of FGFR3 as possible treatments to normalize bone growth in achondroplasia. They include strategies to interfere with FGFR3 synthesis, block its activation, inhibit its tyrosine kinase activity, promote its degradation, and antagonize its downstream signals. These treatment modalities include FGFR3 kinase inhibitors and gamma-secretase that modulate FGFR3 cleavage and nuclear function. Another valuable therapeutic candidate in the treatment of achondroplasia is CNP that works as an antagonist to FGFR3 signal. A previous study revealed that transgenic mice overexpressing brain natriuretic peptide (BNP) in the liver exhibited postnatal skeletal overgrowth with elongation of long bone growth plates [112]. Another study showed that CNP is more potent than BNP in stimulating bone growth by using tibial organ culture experiments, suggesting that CNP was the physiological ligand in growing bones [113]. Global knockout of CNP in mice showed severe postnatal dwarfism that was rescued after crossing with mice overexpressing CNP from a transgene driven by the cartilage-specific COL2A1 promoter [114]. These results confirmed the stimulatory effects of CNP on endochondral ossification in vivo. To explore the beneficial effects of CNP in treating achondroplasia, mice overexpressing CNP in cartilage were crossed with mice displaying an achondroplastic phenotype due to overexpression mutation of FGFR3 [115]. Interestingly, the skeletal growth defect in the achondroplastic mice was corrected by the local overexpression of CNP. The results suggested that CNP antagonizes the active FGFR3 possibly by inhibition of MAPK-mediated FGFR3 signaling (Figure 13).


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)

Achondroplasia pathogenesis and potential therapeutic interventions.
© Copyright Policy
Related In: Results  -  Collection

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

fig13: Achondroplasia pathogenesis and potential therapeutic interventions.
Mentions: Treatment. A number of therapeutic approaches have been attempted to reduce excessive activation of FGFR3 as possible treatments to normalize bone growth in achondroplasia. They include strategies to interfere with FGFR3 synthesis, block its activation, inhibit its tyrosine kinase activity, promote its degradation, and antagonize its downstream signals. These treatment modalities include FGFR3 kinase inhibitors and gamma-secretase that modulate FGFR3 cleavage and nuclear function. Another valuable therapeutic candidate in the treatment of achondroplasia is CNP that works as an antagonist to FGFR3 signal. A previous study revealed that transgenic mice overexpressing brain natriuretic peptide (BNP) in the liver exhibited postnatal skeletal overgrowth with elongation of long bone growth plates [112]. Another study showed that CNP is more potent than BNP in stimulating bone growth by using tibial organ culture experiments, suggesting that CNP was the physiological ligand in growing bones [113]. Global knockout of CNP in mice showed severe postnatal dwarfism that was rescued after crossing with mice overexpressing CNP from a transgene driven by the cartilage-specific COL2A1 promoter [114]. These results confirmed the stimulatory effects of CNP on endochondral ossification in vivo. To explore the beneficial effects of CNP in treating achondroplasia, mice overexpressing CNP in cartilage were crossed with mice displaying an achondroplastic phenotype due to overexpression mutation of FGFR3 [115]. Interestingly, the skeletal growth defect in the achondroplastic mice was corrected by the local overexpression of CNP. The results suggested that CNP antagonizes the active FGFR3 possibly by inhibition of MAPK-mediated FGFR3 signaling (Figure 13).

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