Signalling by fibroblast growth factor receptor 3 and parathyroid hormone-related peptide coordinate cartilage and bone development
Signalling by fibroblast growth factor receptor 3 and parathyroid hormone-related peptide coordinate cartilage and bone development
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DOI：
10.1016/j.bone.2003.08.009
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发表时间：
2004-01-01
期刊：
影响因子：
4.1
通讯作者：
Henderson, JE
中科院分区：
文献类型：
--
作者：
Amizuka, N;Davidson, D;Henderson, JE
骨发育受保守的信号通路调节，这些信号通路与多功能生长因子及其高亲和力受体相关。甲状旁腺素相关肽（PTHrP）和成纤维细胞生长因子受体3（FGFR 3）在软骨内骨形成过程中对软骨细胞的复制、成熟和死亡起关键作用，有时是互补作用。为了进一步了解这些途径如何协调软骨和骨发育，我们产生了缺乏PTHrP和FGFR 3表达的小鼠。复合突变小鼠的表型类似于其PTHrP缺陷的同窝出生的新生儿致死率，面部畸形和四肢缩短。PTHrP（- / -）和PTHrP（- / -）/FGFR 3（- / -）小鼠发育中的骺软骨中PTHrP的缺失导致显性低增殖表型。然而，在PTHrP（-）（/）（-）小鼠的肥大软骨细胞中存在非肥大细胞和在PTHrP（- / -）/FGFR 3（-）（/）（-）小鼠的肥大区中观察到的过度凋亡等异常在PTHrP（- / -）/FGFR 3（-）（-）小鼠中不存在。此外，在单一和复合突变小鼠中FGFR 3的缺乏导致血管内皮生长因子（VEGF）的表达减少和肥大软骨细胞的深度增加。这些观察结果表明，FGFR 3缺陷可以挽救PTHrP缺陷小鼠中观察到的一些缺陷，并且它在软骨细胞分化和肥大的调节中起重要作用。这些研究支持PTHrP在肢体发育过程中调节增殖细胞库中的主导作用，并表明FGFR 3的信号传导在软骨-骨交界处的软骨成熟和血管侵袭中起着更突出的作用。(C)2003爱思唯尔公司All rights reserved.
Bone development is regulated by conserved signalling pathways that are linked to multifunctional growth factors and their high affinity receptors. Parathyroid hormone-related peptide (PTHrP) and fibroblast growth factor receptor 3 (FGFR3) have been shown to play pivotal, and sometimes complementary, roles in the replication, maturation and death of chondrocytes during endochondral bone formation. To gain further insight into how these pathways coordinate cartilage and bone development, we generated mice lacking expression of both PTHrP and FGFR3. The phenotype of compound mutant mice resembled that of their PTHrP-deficient littermates with respect to neonatal lethality, facial dysmorphism and foreshortening of the limbs. The absence of PTHrP in the developing epiphyseal cartilage of PTHrP(- / -) and PTHrP(- / -) /FGFR3(- / -) mice resulted in a dominant hypo-proliferative phenotype. However, abnormalities such as the presence of nonhypertrophic cells among hypertrophic chondrocytes and excessive apoptosis seen in the hypertrophic zone of PTHrP(-) (/) (-) mice were absent in the PTHrP(- / -) /FGFR3(-) (/) (-) mice. Furthermore, the absence of FGFR3 in single and compound mutant mice led to decreased expression of vascular endothelial growth factor (VEGF) and an increase in depth of hypertrophic chondrocytes. These observations indicate that FGFR3 deficiency can rescue some of the defects seen in PTHrP-deficient mice and that it plays an important role in the regulation of chondrocyte differentiation and hypertrophy. These studies support a dominant role for PTHrP in regulating the pool of proliferating cells during limb development and suggest that signalling by FGFR3 plays a more prominent role in cartilage maturation and vascular invasion at the chondro-osseous junction. (C) 2003 Elsevier Inc. All rights reserved.