The critical role of the epidermal growth factor receptor in endochondral ossification.
The critical role of the epidermal growth factor receptor in endochondral ossification.
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DOI：
10.1002/jbmr.502
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发表时间：
2011-11
影响因子：
6.2
通讯作者：
Qin, Ling
中科院分区：
文献类型：
--
作者：
Zhang, Xianrong;Siclari, Valerie A.;Lan, Shenghui;Zhu, Ji;Koyama, Eiki;Dupuis, Holly L.;Enomoto-Iwamoto, Motomi;Beier, Frank;Qin, Ling
小鼠表皮生长因子受体（EGFR）活性的丧失改变了生长板的发育，损害了软骨内骨化，并延缓了生长。然而，EGFR调节软骨内骨形成的详细机制尚不清楚。在这里，我们表明，EGFR特异性小分子抑制剂，吉非替尼，给药到1个月大的大鼠7天，产生深刻的缺陷，在长骨生长板软骨的特点是骺生长板增厚和大量积累的肥大软骨细胞。免疫染色显示生长板软骨细胞表达EGFR，但内皮细胞和破骨细胞几乎不表达。吉非替尼没有改变软骨细胞增殖或分化和血管侵入肥大软骨。然而，由于生长板中RANKL表达降低，软骨-骨交界处的破骨细胞募集和分化减弱。此外，吉非替尼治疗抑制基质金属蛋白酶（MMP 9，13和14）的表达，增加胶原纤维的量，并减少降解的细胞外基质产物在生长板。在体外，EGFR配体TGFα强烈刺激原代软骨细胞中RANKL、MMP 9和MMP 13的表达，并抑制OPG的表达。此外，软骨特异性EGFR失活的小鼠模型表现出类似的肥大性软骨增大表型。总之，我们的数据表明，EGFR信号支持破骨细胞在软骨-骨交界处，并促进生长板中的MMPs的软骨表达。因此，我们得出结论，EGFR信号在软骨内骨化过程中生长板软骨细胞外基质重塑成骨中起着至关重要的作用。
Loss of epidermal growth factor receptor (EGFR) activity in mice alters growth plate development, impairs endochondral ossification, and retards growth. However, the detailed mechanism by which EGFR regulates endochondral bone formation is unknown. Here, we show that administration of an EGFR-specific small molecule inhibitor, gefitinib, into 1-month-old rats for 7 days produced profound defects in long bone growth plate cartilage characterized by epiphyseal growth plate thickening and massive accumulation of hypertrophic chondrocytes. Immunostaining demonstrated that growth plate chondrocytes express EGFR but endothelial cells and osteoclasts show little to no expression. Gefitinib did not alter chondrocyte proliferation or differentiation and vascular invasion into the hypertrophic cartilage. However, osteoclast recruitment and differentiation at the chondro-osseous junction was attenuated due to decreased RANKL expression in the growth plate. Moreover, gefitinib treatment inhibited the expression of matrix metalloproteinases (MMP9, 13, and 14), increased the amount of collagen fibrils, and decreased degraded extracellular matrix products in the growth plate. In vitro, the EGFR ligand TGFα strongly stimulated RANKL, MMP9 and MMP13 expression and suppressed OPG expression in primary chondrocytes. In addition, a mouse model of cartilage-specific EGFR inactivation exhibited a similar phenotype of hypertrophic cartilage enlargement. Together, our data demonstrate that EGFR signaling supports osteoclastogenesis at the chondro-osseous junction and promotes chondrogenic expression of MMPs in the growth plate. Therefore, we conclude that EGFR signaling plays an essential role in the remodeling of growth plate cartilage extracellular matrix into bone during endochondral ossification.
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影响因子：
64.8
作者：
MIETTINEN, PJ;BERGER, JE;DERYNCK, R
通讯作者：
DERYNCK, R
影响因子：
4.8
作者：
Chan, SY;Wong, RWC
通讯作者：
Wong, RWC
影响因子：
2.5
作者：
Lee, D;Cross, SH;Threadgill, DW
通讯作者：
Threadgill, DW
影响因子：
15.9
作者：
Masuyama, Ritsuko;Stockmans, Ingrid;Carmeliet, Geert
通讯作者：
Carmeliet, Geert
DOI：
10.1083/jcb.151.4.879
发表时间：
2000-11-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Engsig MT;Chen QJ;Vu TH;Pedersen AC;Therkidsen B;Lund LR;Henriksen K;Lenhard T;Foged NT;Werb Z;Delaissé JM
通讯作者：
Delaissé JM