Altered endochondral bone development in matrix metalloproteinase 13-deficient mice
Altered endochondral bone development in matrix metalloproteinase 13-deficient mice
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DOI：
10.1242/dev.01461
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发表时间：
2004-12-01
期刊：
影响因子：
4.6
通讯作者：
Werb, Z
中科院分区：
文献类型：
--
作者：
Stickens, D;Behonick, DJ;Werb, Z
细胞外基质（ECM）分子的组装和降解是骨发育过程中的关键过程。在这项研究中，我们发现ECM重塑是软骨内骨形成的关键限速步骤。基质金属蛋白酶（MMP）13（胶原酶3）由于在生长板的终末肥大软骨细胞中表达而在骨形成和重塑中起着至关重要的作用。p和成骨细胞中。此外，人类MMP 13基因的突变导致脊柱干骺端发育不良的密苏里州变体。Mmp13在小鼠中通过同源重组失活导致骨骼生长板发育异常。软骨细胞分化正常，但其退出生长板延迟。Mmp13-null生长板表型的严重程度增加，直到约5周龄，并在12周龄时完全消退。mmp13基因敲除小鼠的骨小梁增加，并持续数月。软骨细胞和成骨细胞中Mmp13的有条件失活表明，骨小梁的增加独立于由晚期肥大软骨细胞中Mmp13缺乏引起的软骨ECM降解。我们的研究确定了软骨ECM的两个主要成分，II型胶原蛋白和聚集蛋白聚糖，作为MMP 13的体内底物。我们发现软骨胶原蛋白和聚集蛋白聚糖的降解是一个协调的过程，其中MMP 13与MMP 9协同作用。缺乏MMP 13和MMP 9的小鼠具有严重受损的软骨内骨，其特征在于ECM重塑减少、软骨细胞存活延长、血管募集延迟和骨小梁形成缺陷（导致骨急剧缩短）。这些数据支持的假设，适当的ECM重塑是占主导地位的限速过程中的程序性细胞死亡，血管生成和成骨细胞招聘在正常的骨骼形态发生。
The assembly and degradation of extracellular matrix (ECM) molecules are crucial processes during bone development. In this study, we show that ECM remodeling is a critical rate-limiting step in endochondral bone formation. Matrix metalloproteinase (MMP) 13 (collagenase 3) is poised to play a crucial role in bone formation and remodeling because of its expression both in terminal hypertrophic chondrocytes in the growth plate. p and in osteoblasts. Moreover, a mutation in the human MMP13 gene causes the Missouri variant of spondyloepimetaphyseal dysplasia. Inactivation of Mmp13 in mice through homologous recombination led to abnormal skeletal growth plate development. Chondrocytes differentiated normally but their exit from the growth plate was delayed. The severity of the Mmp13-null growth plate phenotype increased until about 5 weeks and completely resolved by 12 weeks of age. Mmp13-null mice had increased trabecular bone, which persisted for months. Conditional inactivation of Mmp13 in chondrocytes and osteoblasts showed that increases in trabecular bone occur independently of the improper cartilage ECM degradation caused by Mmp13 deficiency in late hypertrophic chondrocytes. Our studies identified the two major components of the cartilage ECM, collagen type II and aggrecan, as in vivo substrates for MMP13. We found that degradation of cartilage collagen and aggrecan is a coordinated process in which MMP13 works synergistically with MMP9. Mice lacking both MMP13 and MMP9 had severely impaired endochondral bone, characterized by diminished ECM remodeling, prolonged chondrocyte survival, delayed vascular recruitment and defective trabecular bone formation (resulting in drastically shortened bones). These data support the hypothesis that proper ECM remodeling is the dominant rate-limiting process for programmed cell death, angiogenesis and osteoblast recruitment during normal skeletal morphogenesis.