Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse.
Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse.
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DOI：
10.1016/j.ydbio.2009.01.031
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发表时间：
2009-04-15
影响因子：
2.7
通讯作者：
Iwamoto, Masahiro
中科院分区：
文献类型：
--
作者：
Williams, Julie A.;Kondo, Naoki;Okabe, Takahiro;Takeshita, Nobuo;Pilchak, Diane M.;Koyama, Eiki;Ochiai, Takanaga;Jensen, Deborah;Chu, Mon-Li;Kane, Maureen A.;Napoli, Joseph L.;Enomoto-Iwamoto, Motomi;Ghyselinck, Norbert;Chambon, Pierre;Pacifici, Maurizio;Iwamoto, Masahiro
视黄酸受体 α、β 和 γ（RARα、RARβ 和 RARγ）是调节胚胎发生过程中基本过程的核激素受体，但它们在骨骼发育和生长中的作用仍不清楚。为了研究骨骼特异性 RAR 功能，我们创建了软骨中 RAR 表达缺陷的条件小鼠突变体。我们发现缺乏 RARα 和 RARγ（或 RARβ 和 RARγ）的小鼠在出生后约 3 周表现出明显的严重生长迟缓。它们的生长板有缺陷，重要的是，聚集蛋白聚糖的表达和含量显着下降。然而，缺乏 RARα 和 RARβ 的小鼠实际上是正常的，这表明 RARγ 是必需的。具有良好的相关性，我们发现 RARγ 是小鼠生长板中表达最强烈的 RAR，其表达表征了聚集蛋白聚糖也强烈表达的增殖和肥大前区域。由于是无血管的，这些区域缺乏内源性视黄醇，因此 RARγ 可能发挥无配体的阻遏功能。事实上，我们的数据表明： 在无视黄醇培养条件下，软骨细胞中 RARγ 过表达可增强聚集蛋白聚糖的产生；辅阻遏物 Zac1 或增强 RAR 阻遏物功能的药物可进一步促进产量； RAR/Zac1 对聚集蛋白聚糖表达的作用可能涉及 Sox 蛋白。总之，我们的数据表明，RAR，尤其是 RARγ，在生长板功能和骨骼生长中发挥着以前未被认识到的作用，并调节聚集蛋白聚糖的表达和含量。由于聚集蛋白聚糖对于生长板功能至关重要，因此 RAR 突变小鼠中聚集蛋白聚糖的缺乏可能直接导致其生长迟缓。
The retinoic acid receptors α, β and γ (RARα, RARβ and RARγ) are nuclear hormone receptors that regulate fundamental processes during embryogenesis, but their roles in skeletal development and growth remain unclear. To study skeletal-specific RAR function, we created conditional mouse mutants deficient in RAR expression in cartilage. We find that mice deficient in RARα and RARγ (or RARβ and RARγ) exhibit severe growth retardation obvious by about 3 weeks postnatally. Their growth plates are defective and, importantly, display a major drop in aggrecan expression and content. Mice deficient in RARα and RARβ, however, are virtually normal, suggesting that RARγ is essential. In good correlation, we find that RARγ is the most strongly expressed RAR in mouse growth plate and its expression characterizes the proliferative and pre-hypertrophic zones where aggrecan is strongly expressed also. By being avascular, those zones lack endogenous retinoids and thus RARγ is likely to exert ligand-less repressor function. Indeed, our data indicate that: aggrecan production is enhanced by RARγ over-expression in chondrocytes under retinoid-free culture conditions; production is further boosted by corepressor Zac1 or pharmacologic agents that enhance RAR repressor function; and RAR/Zac1 function on aggrecan expression may involve Sox proteins. In sum, our data reveal that RARs, and RARγ in particular, exert previously unappreciated roles in growth plate function and skeletal growth and regulate aggrecan expression and content. Since aggrecan is critical for growth plate function, its deficiency in RAR-mutant mice is likely to have contributed directly to their growth retardation.
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影响因子：
64.8
作者：
Jepsen, Kristen;Solum, Derek;Rosenfeld, Michael G.
通讯作者：
Rosenfeld, Michael G.
影响因子：
1.5
作者：
Chapellier, B;Mark, M;Ghyselinck, NB
通讯作者：
Ghyselinck, NB
影响因子：
64.8
作者：
HORLEIN, AJ;NAAR, AM;ROSENFELD, MG
通讯作者：
ROSENFELD, MG
影响因子：
64.5
作者：
Jepsen, K;Hermanson, O;Rosenfeld, MG
通讯作者：
Rosenfeld, MG
影响因子：
4.8
作者：
Bour, G;Plassat, JL;Rochette-Egly, C
通讯作者：
Rochette-Egly, C