Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia.
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.
State Key Laboratory of Trauma, Burns and Combined Injury, Center of Bone Metabolism and Repair, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Yangli
Y
Xie
Nan
N
Su
Min
M
Jin
Huabing
H
Qi
Junbao
J
Yang
Can
C
Li
Xiaolan
X
Du
Fengtao
F
Luo
Bo
B
Chen
Yue
Y
Shen
Haiyang
H
Huang
Cory J
CJ
Xian
Chuxia
C
Deng
Lin
L
Chen
D000130:Achondroplasia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001846:Bone Development / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D018878:Limb Buds / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D019379:Teriparatide / Q000008:administration & dosage* / Q000494:pharmacology; D013796:Thanatophoric Dysplasia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D046509:Tissue Culture Techniques
D050071:Bone Density Conservation Agents; D044162:Parathyroid Hormone-Related Protein; D019379:Teriparatide; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3