The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early onset osteoarthritis
The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early onset osteoarthritis
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col11a2损失对关节的机械影响；
DOI：
10.1101/302307
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Lawrence E
中科院分区：
文献类型：
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作者：
Lawrence E
胶原蛋白是软骨的主要结构成分，编码XI型胶原蛋白的基因突变与严重的骨骼发育不良（纤维软骨形成和Stickler综合征）和早发性骨关节炎（OA）相关。在骨骼发育过程中，缺乏XI型胶原对细胞行为和机械性能的影响尚不清楚。我们研究了斑马鱼突变体col 11 a2，并评估了软骨，骨发育和机械性能，以解决这个问题。我们发现，incol 11 a2突变体，II型胶原蛋白，但过早降解成熟的软骨和异位表达的关节。这些变化与骨和软骨硬度增加相关;使用原子力显微镜定量。在突变体中，颌骨关节中的骨骼雏形末端区域更宽，中间区域更小。这些形状和材料特性的差异会影响关节功能和机械性能，我们使用有限元分析进行了建模。最后，我们发现col 11 a2杂合子携带者进入成年期，但表现出严重的早发性OA的迹象。综上所述，我们的数据证明了XI型胶原蛋白在维持软骨基质的特性方面的关键作用;当失去时，会导致细胞行为的改变，从而引起关节病理学。本文是Theo Murphy会议问题“发育力学”的一部分。
Collagen is the major structural component of cartilage, and mutations in the genes encoding type XI collagen are associated with severe skeletal dysplasias (fibrochondrogenesis and Stickler syndrome) and early-onset osteoarthritis (OA). The impact of the lack of type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant forcol11a2and evaluated cartilage, bone development and mechanical properties to address this. We show that incol11a2mutants, type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using atomic force microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint is broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using finite element analyses. Finally, we show thatcol11a2heterozygous carriers reach adulthood but show signs of severe early-onset OA. Taken together, our data demonstrate a key role for type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.