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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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CMD pathogenesis and potential therapeutic interventions.
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fig12: CMD pathogenesis and potential therapeutic interventions.

Mentions: Pathogenesis of CMD. All CMD cases with known molecular diagnosis have so far been linked to ankh nonsense mutations on chromosome 6 that underlie increased intracellular and decreased extracellular pyrophosphates (PPi) [82, 86, 88, 89]. Recent studies of CMD also point to the role of PPi in the regulation of the bone modeling/remodeling process. The ANKH protein is type II transmembrane with 10–12 helices, spanning the outer cell membrane, and is associated with PPi efflux (Figure 10). Most of the ankh mutations are located in cytoplasmic domains close to the C-terminus [82, 86]. PPi is a major inhibitor of physiologic, pathologic tissue calcification and bone mineralization. Intracellular PPi is generated and stored largely in mitochondria, but it is also detected in endoplasmic reticulum and Golgi [90–94]. The extracellular PPi concentration in the skeletal tissue is determined by several types of cell membrane proteins: ectoenzyme PC1, which generates PPi from ATP, tissue nonspecific alkaline phosphatase (TNAP), which hydrolyzes PPi into two inorganic phosphates (Pi), and ANKH, which is involved in PPi efflux (Figure 11). While the functional role of intracellular PPi in mammalian cells remains elusive, extracellular PPi has been extensively studied for its inhibitory role in tissue calcification. Extracellular PPi directly binds to the surface of basic calcium phosphate hydroxyapatites and interferes with propagation of crystal formation, contributing to the formation of poorly ordered bone crystal structure [95, 96]. In addition, exogenous PPi at micromolar concentrations stimulates the expression of osteopontin, which is a negative regulator of mineralization, and inhibits the enzymatic activity of tissue nonspecific alkaline phosphatase (ALP) in osteoblast cultures [96, 97]. Thus, a decrease in extracellular PPi may hinder normal bone remodeling, for instance, by inhibiting osteoclast differentiation or activity. In support of this notion, bone marrow-derived monocytes (BMMs) from a CMD knock-in mouse (p.Phe377del in ank) poorly differentiated to osteoclasts in cultures, compared to those from wild type mice [98]. Consistent with the mouse data, the number of bone marrow-derived osteoclast-like cells from a CMD patient was only 40% of a normal individual, and they lacked osteoclast-specific vacuolar proton pump and the ability to absorb a dentin slice [99]. The ANKH protein may have also other, unknown functions (Figure 12).


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)

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

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

fig12: CMD pathogenesis and potential therapeutic interventions.
Mentions: Pathogenesis of CMD. All CMD cases with known molecular diagnosis have so far been linked to ankh nonsense mutations on chromosome 6 that underlie increased intracellular and decreased extracellular pyrophosphates (PPi) [82, 86, 88, 89]. Recent studies of CMD also point to the role of PPi in the regulation of the bone modeling/remodeling process. The ANKH protein is type II transmembrane with 10–12 helices, spanning the outer cell membrane, and is associated with PPi efflux (Figure 10). Most of the ankh mutations are located in cytoplasmic domains close to the C-terminus [82, 86]. PPi is a major inhibitor of physiologic, pathologic tissue calcification and bone mineralization. Intracellular PPi is generated and stored largely in mitochondria, but it is also detected in endoplasmic reticulum and Golgi [90–94]. The extracellular PPi concentration in the skeletal tissue is determined by several types of cell membrane proteins: ectoenzyme PC1, which generates PPi from ATP, tissue nonspecific alkaline phosphatase (TNAP), which hydrolyzes PPi into two inorganic phosphates (Pi), and ANKH, which is involved in PPi efflux (Figure 11). While the functional role of intracellular PPi in mammalian cells remains elusive, extracellular PPi has been extensively studied for its inhibitory role in tissue calcification. Extracellular PPi directly binds to the surface of basic calcium phosphate hydroxyapatites and interferes with propagation of crystal formation, contributing to the formation of poorly ordered bone crystal structure [95, 96]. In addition, exogenous PPi at micromolar concentrations stimulates the expression of osteopontin, which is a negative regulator of mineralization, and inhibits the enzymatic activity of tissue nonspecific alkaline phosphatase (ALP) in osteoblast cultures [96, 97]. Thus, a decrease in extracellular PPi may hinder normal bone remodeling, for instance, by inhibiting osteoclast differentiation or activity. In support of this notion, bone marrow-derived monocytes (BMMs) from a CMD knock-in mouse (p.Phe377del in ank) poorly differentiated to osteoclasts in cultures, compared to those from wild type mice [98]. Consistent with the mouse data, the number of bone marrow-derived osteoclast-like cells from a CMD patient was only 40% of a normal individual, and they lacked osteoclast-specific vacuolar proton pump and the ability to absorb a dentin slice [99]. The ANKH protein may have also other, unknown functions (Figure 12).

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