Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy
Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy
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DOI：
10.1242/dev.018044
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发表时间：
2008-06-01
期刊：
影响因子：
4.6
通讯作者：
Yang, Yingzi
中科院分区：
文献类型：
--
作者：
Mak, Kinglun Kingston;Kronenberg, Henry M.;Yang, Yingzi
软骨细胞肥大是软骨内骨形成所必需的过程。软骨细胞肥大的适当调节也是出生后软骨稳态所必需的。Indian hedgehog（Ihh）和PTHrP信号通过形成负反馈环在调节软骨细胞肥大的发生中起关键作用，其中Ihh信号通过控制PTHrP表达来调节软骨细胞肥大。为了了解Ihh信号在调节软骨细胞肥大中是否具有PTHrP独立作用，我们在软骨内骨骼发育过程中，在没有PTHrP的情况下激活和灭活Ihh信号。我们发现，通过在体外用音刺猬（Shh）蛋白处理PTHrP（-/-）肢体外植体，或在PTHrP（-/-）胚胎的软骨中过表达Ihh或使刺猬（Hh）信号的负调节因子patch 1（Ptch 1）失活，在发育中的软骨中上调Ihh信号，加速PTHrP（-/-）胚胎的软骨细胞肥大。相反，当Hh信号被环巴胺阻断或通过去除Smoothened（Smo）（Hh信号的正调节剂）时，PTHrP（-/-）胚胎中的软骨细胞肥大被延迟。此外，我们发现，在出生后的软骨Hh信号的上调导致加速软骨细胞肥大在继发性骨化，这反过来又导致关节软骨减少。我们的研究结果揭示了Ihh信号在促进软骨细胞肥大中独立于PTHrP的新作用，PTHrP在出生后软骨发育和稳态中特别重要。此外，我们发现软骨中的骨形态发生蛋白（Bmp）和Wnt/β-连环蛋白信号都可能介导上调的Ihh信号在促进软骨细胞肥大中的作用。
Chondrocyte hypertrophy is an essential process required for endochondral bone formation. Proper regulation of chondrocyte hypertrophy is also required in postnatal cartilage homeostasis. Indian hedgehog (Ihh) and PTHrP signaling play crucial roles in regulating the onset of chondrocyte hypertrophy by forming a negative feedback loop, in which Ihh signaling regulates chondrocyte hypertrophy by controlling PTHrP expression. To understand whether there is a PTHrP-independent role of Ihh signaling in regulating chondrocyte hypertrophy, we have both activated and inactivated Ihh signaling in the absence of PTHrP during endochondral skeletal development. We found that upregulating Ihh signaling in the developing cartilage by treating PTHrP(-/-) limb explants with sonic hedgehog (Shh) protein in vitro, or overexpressing Ihh in the cartilage of PTHrP(-/-) embryos or inactivating patched 1 (Ptch1), a negative regulator of hedgehog (Hh) signaling, accelerated chondrocyte hypertrophy in the PTHrP(-/-) embryos. Conversely, when Hh signaling was blocked by cyclopamine or by removing Smoothened (Smo), a positive regulator of Hh signaling, chondrocyte hypertrophy was delayed in the PTHrP(-/-) embryo. Furthermore, we show that upregulated Hh signaling in the postnatal cartilage led to accelerated chondrocyte hypertrophy during secondary ossification, which in turn caused reduction of joint cartilage. Our results revealed a novel role of Ihh signaling in promoting chondrocyte hypertrophy independently of PTHrP, which is particularly important in postnatal cartilage development and homeostasis. In addition, we found that bone morphogenetic protein (Bmp) and Wnt/beta-catenin signaling in the cartilage may both mediate the effect of upregulated Ihh signaling in promoting chondrocyte hypertrophy.