Abstract
Achondroplasia (ACH) and thanatophoric dysplasia (TD) are caused by gain-of-function mutations of fibroblast growth factor receptor 3 (FGFR3) and they are the most common forms of dwarfism and lethal dwarfism, respectively. Currently, there are few effective treatments for ACH. For the neonatal lethality of TD patients, no practical effective therapies are available. We here showed that systemic intermittent PTH (1-34) injection can rescue the lethal phenotype of TD type II (TDII) mice and significantly alleviate the retarded skeleton development of ACH mice. PTH-treated ACH mice had longer naso-anal length than ACH control mice, and the bone lengths of humeri and tibiae were rescued to be comparable with those of wild-type control mice. Our study also found that the premature fusion of cranial synchondroses in ACH mice was partially corrected after the PTH (1-34) treatment, suggesting that the PTH treatment may rescue the progressive narrowing of neurocentral synchondroses that cannot be readily corrected by surgery. In addition, we found that the PTH treatment can improve the osteopenia and bone structure of ACH mice. The increased expression of PTHrP and down-regulated FGFR3 level may be responsible for the positive effects of PTH on bone phenotype of ACH and TDII mice.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Achondroplasia / drug therapy*
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Achondroplasia / genetics
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Achondroplasia / pathology
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Animals
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Body Weight / drug effects
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Bone Density / drug effects
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Bone Density Conservation Agents / administration & dosage*
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Bone Density Conservation Agents / pharmacology
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Bone Development / drug effects*
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Bone Diseases, Metabolic / drug therapy
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Bone Diseases, Metabolic / genetics
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Bone and Bones / diagnostic imaging
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Bone and Bones / drug effects
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Bone and Bones / pathology
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Cell Differentiation
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Cell Proliferation
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Cells, Cultured
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Chondrocytes / drug effects
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Chondrocytes / physiology
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Drug Evaluation, Preclinical
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Gene Expression
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Gene Expression Regulation
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Humans
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Limb Buds / drug effects
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Limb Buds / pathology
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Mice
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Mice, Transgenic
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Mutation, Missense
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Parathyroid Hormone-Related Protein / genetics
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Parathyroid Hormone-Related Protein / metabolism
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Radiography
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Receptor, Fibroblast Growth Factor, Type 3 / genetics
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Receptor, Fibroblast Growth Factor, Type 3 / metabolism
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Teriparatide / administration & dosage*
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Teriparatide / pharmacology
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Thanatophoric Dysplasia / drug therapy*
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Thanatophoric Dysplasia / genetics
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Thanatophoric Dysplasia / pathology
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Tissue Culture Techniques
Substances
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Bone Density Conservation Agents
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Parathyroid Hormone-Related Protein
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Teriparatide
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Fgfr3 protein, mouse
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Receptor, Fibroblast Growth Factor, Type 3