Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.
Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.
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DOI：
10.1172/jci.insight.168796
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发表时间：
2023-06-22
期刊：
影响因子：
8
通讯作者：
Legeai-Mallet, Laurence
中科院分区：
文献类型：
--
作者：
Loisay, Lea;Komla-Ebri, Davide;Morice, Anne;Heuze, Yann;Viaut, Camille;Seigliere, Amelie de La;Kaci, Nabil;Chan, Danny;Lamouroux, Audrey;Baujat, Genevieve;Bassett, J. H. Duncan;Williams, Graham R.;Legeai-Mallet, Laurence
软骨发育不良（HCH）是一种由成纤维细胞生长因子受体3 （FGFR3）错义突变引起的轻度侏儒症，大多数病例是由杂合的p.Asn540Lys功能获得突变引起的。在这里，我们报道了据我们所知的第一个HCH小鼠模型（Fgfr3Asn534Lys/+）的生成和表征。Fgfr3Asn534Lys/+小鼠表现出进行性侏儒症和颅底联合软骨损伤，导致枕骨大孔形成缺陷。阑尾和中轴骨骼都受到严重影响，我们证明了FGFR3在调节皮质和小梁骨结构中的重要作用。长骨和椎体的骨小梁骨密度（BMD）随着年龄的增长而降低，而胫骨和股骨的骨皮质骨密度（BMD）随着年龄的增长而增加。这些结果表明，Fgfr3Asn534Lys/+小鼠的骨骼，由于FGFR3的激活，表现出骨质疏松症的一些特征。目前的研究结果强调了Fgfr3基因功能获得突变在发育和衰老过程中对长骨建模的不利影响，这对老年软骨发育不良和骨质疏松症患者的治疗具有潜在的意义。
Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.
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影响因子：
4.3
作者：
Hemmatian H;Bakker AD;Klein-Nulend J;van Lenthe GH
通讯作者：
van Lenthe GH
影响因子：
1.4
作者：
Alejandra Arenas, Maria;del Pino, Mariana;Fano, Virginia
通讯作者：
Fano, Virginia
影响因子：
3.5
作者：
Iwata, T;Li, CL;Francomano, CA
通讯作者：
Francomano, CA
影响因子：
15.9
作者：
Chen, L;Adar, R;Deng, CX
通讯作者：
Deng, CX
DOI：
10.1155/2015/459428
发表时间：
2015-01-01
期刊：
Anatomy research international
影响因子：
--
作者：
Kamath, Venkatesh Gokuldas;Asif, Muhammed;Avadhani, Ramakrishna
通讯作者：
Avadhani, Ramakrishna