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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 GSD. Lymphatic and blood endothelial cells (LECs), BECs, and macrophages (Mac) secrete TNFα that stimulate OB to release IL-6. Mac produces VEGF-C and -D that stimulate proliferation of LECs and BECs. Mac also produces VEGF-A, -C, and -D and IL-6 that directly stimulate osteoclast-mediated bone resorption.
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fig3: Schematic diagram of the pathogenesis of GSD. Lymphatic and blood endothelial cells (LECs), BECs, and macrophages (Mac) secrete TNFα that stimulate OB to release IL-6. Mac produces VEGF-C and -D that stimulate proliferation of LECs and BECs. Mac also produces VEGF-A, -C, and -D and IL-6 that directly stimulate osteoclast-mediated bone resorption.

Mentions: The pathogenesis of GD is not well understood and therefore not many therapeutic modalities are currently available. Recent study showed that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) in addition to macrophages secrete TNFα and IL-6 that stimulate osteoclast formation with excessive osteolysis [19]. Macrophages produce VEGF-C and -D that stimulate proliferation of LECs and BECs. Moreover, macrophages produce VEGF-A, -C, and -D and IL-6 that directly stimulate osteoclast differentiation [20] (Figure 3). Furthermore, TNFα secreted by LECs and macrophages inhibits osteoblast differentiation and new bone formation [21]. Devlin et al. [22] demonstrated that the serum from a patient with GD caused increased proliferation of osteoclast-like multinucleated cells when cultured with normal human bone marrow. Furthermore, the levels of IL-6 were significantly higher in the serum of GD patients. This suggests that bone resorption observed in GD could be a direct result of increased multinucleated cell activity due to increased IL-6 levels. Therefore, local inhibition of IL-6 production or administration of a drug such as tocilizumab will be beneficial.


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 GSD. Lymphatic and blood endothelial cells (LECs), BECs, and macrophages (Mac) secrete TNFα that stimulate OB to release IL-6. Mac produces VEGF-C and -D that stimulate proliferation of LECs and BECs. Mac also produces VEGF-A, -C, and -D and IL-6 that directly stimulate osteoclast-mediated bone resorption.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Schematic diagram of the pathogenesis of GSD. Lymphatic and blood endothelial cells (LECs), BECs, and macrophages (Mac) secrete TNFα that stimulate OB to release IL-6. Mac produces VEGF-C and -D that stimulate proliferation of LECs and BECs. Mac also produces VEGF-A, -C, and -D and IL-6 that directly stimulate osteoclast-mediated bone resorption.
Mentions: The pathogenesis of GD is not well understood and therefore not many therapeutic modalities are currently available. Recent study showed that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) in addition to macrophages secrete TNFα and IL-6 that stimulate osteoclast formation with excessive osteolysis [19]. Macrophages produce VEGF-C and -D that stimulate proliferation of LECs and BECs. Moreover, macrophages produce VEGF-A, -C, and -D and IL-6 that directly stimulate osteoclast differentiation [20] (Figure 3). Furthermore, TNFα secreted by LECs and macrophages inhibits osteoblast differentiation and new bone formation [21]. Devlin et al. [22] demonstrated that the serum from a patient with GD caused increased proliferation of osteoclast-like multinucleated cells when cultured with normal human bone marrow. Furthermore, the levels of IL-6 were significantly higher in the serum of GD patients. This suggests that bone resorption observed in GD could be a direct result of increased multinucleated cell activity due to increased IL-6 levels. Therefore, local inhibition of IL-6 production or administration of a drug such as tocilizumab will be beneficial.

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