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J Mol Med (Berl). 2017 Dec;95(12):1303-1313. doi: 10.1007/s00109-017-1602-9. Epub 2017 Oct 23.

Molecular therapeutic strategies for FGFR3 gene-related skeletal dysplasia.

Chen J1,2, Liu J1,2,3, Zhou Y2,4, Liu S1,2,5, Liu G1,2,5, Zuo Y1,2,5, Wu Z2,5,6, Wu N7,8,9, Qiu G10,11,12.

Author information

1
Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China.
2
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
3
Department of Breast Surgical Oncology, National Cancer Center/Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
4
Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
5
Medical Research Center of Orthopaedics, Chinese Academy of Medical Sciences, Beijing, China.
6
Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
7
Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China. dr.wunan@pumch.cn.
8
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China. dr.wunan@pumch.cn.
9
Medical Research Center of Orthopaedics, Chinese Academy of Medical Sciences, Beijing, China. dr.wunan@pumch.cn.
10
Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China. qiuguixingpumch@126.com.
11
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China. qiuguixingpumch@126.com.
12
Medical Research Center of Orthopaedics, Chinese Academy of Medical Sciences, Beijing, China. qiuguixingpumch@126.com.

Abstract

The FGFR3 gene encodes fibroblast growth factor receptor 3 protein, a negative regulator of chondrogenesis. Gain-of-function mutations result in constitutively activated FGFR3, leading to aberrant signal transduction, and accounting for inhibition of chondrocyte proliferation and differentiation. Generally, these pathogenic mutations maintain FGFR3 in an active state and cause diverse phenotypes in patients with skeletal dysplasia. For decades, studies have revealed the molecular mechanisms of constitutively activated FGFR3 and relevant therapeutic strategies. By modulating the FGFR3-induced signalling pathway with methods such as blocking binding between ligands and receptors, blocking tyrosine kinase activities, or antagonising the FGFR3 downstream signalling pathway, these strategies offer the possibility to ameliorate FGFR3 gene-related skeletal dysplasia phenotypes. In this review, we describe the mechanisms of potential therapeutic targets and underlying regulators and then systematically review molecular therapeutic strategies for FGFR3 gene-related skeletal dysplasia based on current knowledge.

KEYWORDS:

Fibroblast growth factor receptor 3 (FGFR3); Molecular therapy; Signal transduction; Skeletal dysplasia

PMID:
29063142
DOI:
10.1007/s00109-017-1602-9
[Indexed for MEDLINE]

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