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关节软骨细胞中的初级纤毛缺失会导致 Gli3 抑制因子与激活因子的比例降低、 Hedgehog 信号通路激活，以及出现早期骨关节炎的症状。

Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis.

机构信息

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.

出版信息

Osteoarthritis Cartilage. 2012 Feb;20(2):152-61. doi: 10.1016/j.joca.2011.11.009. Epub 2011 Nov 27.

DOI:10.1016/j.joca.2011.11.009
PMID:22173325
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3260404/
Abstract

OBJECTIVE: Primary cilia are present in almost every cell type including chondrocytes. Studies have shown that defects in primary cilia result in skeletal dysplasia. The purpose of this study was to understand how loss of primary cilia affects articular cartilage. DESIGN: Ift88 encodes a protein that is required for intraflagellar transport and formation of primary cilia. In this study, we used Col2aCre;Ift88(fl/fl) transgenic mice in which primary cilia were deleted in chondrocytes. Col2aCre;Ift88(fl/fl) articular cartilage was characterized by histological staining, real time RT-PCR, and microindentation. Hedgehog (Hh) signaling was measured by expression of Ptch1 and Gli1 mRNA. The levels of Gli3 proteins were determined by western blot. RESULTS: Col2aCre;Ift88(fl/fl) articular cartilage was thicker and had increased cell density, likely due to decreased apoptosis during cartilage remodeling. Mutant articular cartilage also showed increased expression of osteoarthritis (OA) markers including Mmp13, Adamts5, ColX, and Runx2. OA was also evident by reduced stiffness in mutant cartilage as measured by microindentation. Up-regulation of Hh signaling, which has been associated with OA, was present in mutant articular cartilage as measured by expression of Ptch1 and Gli1. Col2aCre;Ift88(fl/fl) cartilage also demonstrated reduced Gli3 repressor to activator ratio. CONCLUSION: Our results indicate that primary cilia are required for normal development and maintenance of articular cartilage. It was shown that primary cilia are required for processing full length Gli3 to the truncated repressor form. We propose that OA symptoms in Col2aCre;Ift88(fl/fl) cartilage are due to reduced Hh signal repression by Gli3.

摘要

目的：初级纤毛存在于几乎所有细胞类型中，包括软骨细胞。研究表明，初级纤毛缺陷会导致骨骼发育不良。本研究旨在了解初级纤毛缺失如何影响关节软骨。

设计：IFT88 编码一种蛋白，该蛋白对于鞭毛内运输和初级纤毛的形成是必需的。在这项研究中，我们使用 Col2aCre;Ift88(fl/fl) 转基因小鼠，其中软骨细胞中的初级纤毛被删除。通过组织学染色、实时 RT-PCR 和微压痕分析来表征 Col2aCre;Ift88(fl/fl) 关节软骨。通过 Ptch1 和 Gli1 mRNA 的表达来测量 Hedgehog（Hh）信号。通过 Western blot 测定 Gli3 蛋白水平。

结果：Col2aCre;Ift88(fl/fl) 关节软骨较厚，细胞密度增加，这可能是由于软骨重塑过程中凋亡减少所致。突变型关节软骨还表现出骨关节炎（OA）标志物的表达增加，包括 Mmp13、Adamts5、ColX 和 Runx2。通过微压痕测量，突变型软骨的刚度降低也表明 OA 存在。通过 Ptch1 和 Gli1 的表达，在突变型关节软骨中存在与 OA 相关的 Hh 信号上调。Col2aCre;Ift88(fl/fl) 软骨也表现出Gli3 抑制剂与激活剂比例降低。

结论：我们的结果表明，初级纤毛对于关节软骨的正常发育和维持是必需的。结果表明，初级纤毛对于全长 Gli3 加工成截短的抑制剂形式是必需的。我们提出，Col2aCre;Ift88(fl/fl) 软骨中的 OA 症状是由于 Gli3 对 Hh 信号的抑制作用降低所致。

相似文献

[1]
Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis.

Osteoarthritis Cartilage. 2011-11-27

[2]
Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation.

Mol Cell Biol. 2010-2-12

[3]
Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes.

Oncogene. 2012-12-17

[4]
Depletion of chondrocyte primary cilia reduces the compressive modulus of articular cartilage.

J Biomech. 2013-12-4

[5]
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Arthritis Rheumatol. 2022-1

[6]
The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia.

Hum Mol Genet. 2012-10-1

[7]
α-Catenin inhibits β-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity and collagen type II expression in articular chondrocytes through formation of Gli3R.α-catenin.β-catenin ternary complex.

J Biol Chem. 2012-2-1

[8]
Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling.

FASEB J. 2016-2

[9]
Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance.

Osteoarthritis Cartilage. 2016-4

[10]
Intraflagellar transport protein 88 interacts with polycystin 2 to regulate mechanosensitive hedgehog signaling in mandibular condylar chondrocytes.

Arch Oral Biol. 2022-11

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Adv Sci (Weinh). 2025-6

[2]
Constructing condylar cartilage organoid to explore primary cilia functions.

Heliyon. 2024-8-13

[3]
Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation.

Front Pharmacol. 2024-7-11

[4]
LIPUS regulates the progression of knee osteoarthritis in mice through primary cilia-mediated TRPV4 channels.

Apoptosis. 2024-6

[5]
[Piezo1 Mediates the Regulation of Substrate Stiffness on Primary Cilia in Chondrocytes].

Sichuan Da Xue Xue Bao Yi Xue Ban. 2024-1-20

[6]
Primary cilia are critical for tracheoesophageal septation.

Dev Dyn. 2024-3

[7]
Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α.

Bone Res. 2023-3-3

[8]
The factory, the antenna and the scaffold: the three-way interplay between the Golgi, cilium and extracellular matrix underlying tissue function.

Biol Open. 2023-2-15

[9]
Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers.

Front Physiol. 2022-11-17

[10]
Primary Cilia: A Cellular Regulator of Articular Cartilage Degeneration.

Stem Cells Int. 2022-9-23

本文引用的文献

[1]
Ciliogenesis: building the cell's antenna.

Nat Rev Mol Cell Biol. 2011-4

[2]
Orientation of primary cilia of articular chondrocytes in three-dimensional space.

Anat Rec (Hoboken). 2011-1-12

[3]
Coordinated translocation of mammalian Gli proteins and suppressor of fused to the primary cilium.

PLoS One. 2010-12-29

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The role of the cartilage matrix in osteoarthritis.

Nat Rev Rheumatol. 2010-11-30

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Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders.

Arthritis Res Ther. 2010-9-16

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The primary cilium: a signalling centre during vertebrate development.

Nat Rev Genet. 2010-5

[7]
Mechanical loading modulates chondrocyte primary cilia incidence and length.

Cell Biol Int. 2010-3-24

[8]
Modulating hedgehog signaling can attenuate the severity of osteoarthritis.

Nat Med. 2009-12

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Curr Biol. 2009-7-14

[10]
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Genet Med. 2009-6

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