Mutations in fam20b and xylt1 reveal that cartilage matrix controls timing of endochondral ossification by inhibiting chondrocyte maturation.
Mutations in fam20b and xylt1 reveal that cartilage matrix controls timing of endochondral ossification by inhibiting chondrocyte maturation.
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DOI：
10.1371/journal.pgen.1002246
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发表时间：
2011-08
期刊：
影响因子：
4.5
通讯作者：
Kimmel CB
中科院分区：
文献类型：
--
作者：
Eames BF;Yan YL;Swartz ME;Levic DS;Knapik EW;Postlethwait JH;Kimmel CB
随着时间的推移，分化细胞与其细胞外环境相互作用。软骨细胞将自己植入富含蛋白多糖(PG)的基质中，然后经历一种称为“成熟”的发育转变，当它们表达IHH以诱导覆盖在其上的组织-软骨膜中的骨。在这里，我们问PGs是否调节软骨细胞和软骨膜之间的相互作用，使用斑马鱼突变体揭示软骨PGs抑制软骨细胞成熟，这最终决定了软骨膜骨骼发育的时间。在诱变筛选中，我们分离到一类软骨基质减少，软骨膜增加的突变株。定位克隆发现了两个基因Fam20b和木糖转移酶1(Xylt1)的损伤，这两个基因都编码PG合成酶。突变体不能产生野生型的硫酸软骨素PGs，这种PGs通常在软骨基质中含量丰富，并且比它们的野生型兄弟姐妹更早开始软骨膜的骨形成。原发软骨细胞缺陷可能是由于突变的软骨细胞提前启动成熟，表现为runx2b、10a1和IHH共同源等标志物的早期表达增加，而iHHA突变抑制了PG突变的早期软骨膜，因此可能是继发性的诱导骨表型。超微结构分析显示突变型软骨细胞肥大的早期细胞特征和基质结构异常。我们的体内分析表明，Fam20b和Xylt1参与了PG的合成，我们的体内分析表明，这些基因在软骨基质的产生中发挥功能，并最终调节骨骼发育的时间。软骨模板周围的骨形成是人类主要的骨化过程，它有许多复杂的步骤，必须在空间和时间上进行适当的协调。软骨生成细胞(软骨细胞)首先在自己周围分泌一种软骨基质，这种基质含有丰富的糖衣蛋白质，称为蛋白多糖(PGs)。然后软骨细胞经历一个成熟的过程，在这个过程中它们表达印度刺猬(IHH)，这是一种分泌的蛋白质，可以刺激周围细胞的骨形成。在这里，我们发现软骨基质中的前列腺素调节软骨细胞成熟的时间，表明细胞与它们自己创造的环境之间的相互作用对于正常的骨骼发育至关重要。我们的结论是基于对斑马鱼的分析，斑马鱼的两个不同的PG合成基因突变产生了相同的骨骼缺陷。我们认为，由于软骨PG分泌不足，突变的软骨细胞加快了IHH表达的时间，我们发现这是导致周围细胞骨生成提前和增加的原因。
Differentiating cells interact with their extracellular environment over time. Chondrocytes embed themselves in a proteoglycan (PG)-rich matrix, then undergo a developmental transition, termed “maturation,” when they express ihh to induce bone in the overlying tissue, the perichondrium. Here, we ask whether PGs regulate interactions between chondrocytes and perichondrium, using zebrafish mutants to reveal that cartilage PGs inhibit chondrocyte maturation, which ultimately dictates the timing of perichondral bone development. In a mutagenesis screen, we isolated a class of mutants with decreased cartilage matrix and increased perichondral bone. Positional cloning identified lesions in two genes, fam20b and xylosyltransferase1 (xylt1), both of which encode PG synthesis enzymes. Mutants failed to produce wild-type levels of chondroitin sulfate PGs, which are normally abundant in cartilage matrix, and initiated perichondral bone formation earlier than their wild-type siblings. Primary chondrocyte defects might induce the bone phenotype secondarily, because mutant chondrocytes precociously initiated maturation, showing increased and early expression of such markers as runx2b, collagen type 10a1, and ihh co-orthologs, and ihha mutation suppressed early perichondral bone in PG mutants. Ultrastructural analyses demonstrated aberrant matrix organization and also early cellular features of chondrocyte hypertrophy in mutants. Refining previous in vitro reports, which demonstrated that fam20b and xylt1 were involved in PG synthesis, our in vivo analyses reveal that these genes function in cartilage matrix production and ultimately regulate the timing of skeletal development. The formation of bone around a cartilage template is the predominant ossification process in humans, and it has many complex steps that must be coordinated properly in space and time. Cartilage-producing cells (chondrocytes) first secrete a cartilage matrix around themselves that is rich in sugar-coated proteins called proteoglycans (PGs). Chondrocytes then undergo a maturation process during which they express Indian hedgehog (Ihh), a secreted protein that stimulates bone formation in surrounding cells. Here, we find that PGs in cartilage matrix regulate the timing of chondrocyte maturation, showing that interactions between cells and an environment that they themselves create are crucial for proper skeletal development. Our conclusions are based upon analyses of zebrafish with mutations in two different PG synthesis genes that produce identical skeletal defects. We argue that, as a consequence of deficient cartilage PG production, mutant chondrocytes accelerate the timing of ihh expression, which we show causes early and increased bone production in the surrounding cells.
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影响因子：
1.5
作者：
DeLaurier, April;Eames, B. Frank;Blanco-Sanchez, Bernardo;Peng, Gang;He, Xinjun;Swartz, Mary E.;Ullmann, Bonnie;Westerfield, Monte;Kimmel, Charles B.
通讯作者：
Kimmel, Charles B.
生长板形态发生的Aggrecan调节。
影响因子：
2.7
作者：
Domowicz, Miriam S.;Cortes, Mauricio;Henry, Judith G.;Schwartz, Nancy B.
通讯作者：
Schwartz, Nancy B.
影响因子：
4.6
作者：
Abzhanov, Arhat;Rodda, Stephen J.;Tabin, Clifford J.
通讯作者：
Tabin, Clifford J.
DOI：
10.1073/pnas.82.10.3197
发表时间：
1985-01-01
影响因子：
11.1
作者：
ESKO, JD;STEWART, TE;TAYLOR, WH
通讯作者：
TAYLOR, WH
影响因子：
14.9
作者：
CORPET, F
通讯作者：
CORPET, F