Ferguson C, Alpern E, Miclau T, Helms J A
Department of Orthopaedic Surgery, University of California at San Francisco, 533 Parnassus Ave., San Francisco, USA.
Mech Dev. 1999 Sep;87(1-2):57-66. doi: 10.1016/s0925-4773(99)00142-2.
Bone formation is a continuous process that begins during fetal development and persists throughout life as a remodeling process. In the event of injury, bones heal by generating new bone rather than scar tissue; thus, it can accurately be described as a regenerative process. To elucidate the extent to which fetal skeletal development and skeletal regeneration are similar, we performed a series of detailed expression analyses using a number of genes that regulate key stages of endochondral ossification. They included genes in the indian hedgehog (ihh) and core binding factor 1 (cbfa1) pathways, and genes associated with extracellular matrix remodeling and vascular invasion including vascular endothelial growth factor (VEGF) and matrix metalloproteinase 13 (mmp13). Our analyses suggested that even at the earliest stages of mesenchymal cell condensation, chondrocyte (ihh, cbfa1 and collagen type II-positive) and perichondrial (gli1 and osteocalcin-positive) cell populations were already specified. As chondrocytes matured, they continued to express cbfa1 and ihh whereas cbfa1, osteocalcin and gli1 persisted in presumptive periosteal cells. Later, VEGF and mmp13 transcripts were abundant in chondrocytes as they underwent hypertrophy and terminal differentiation. Based on these expression patterns and available genetic data, we propose a model where Ihh and Cbfa1, together with Gli1 and Osteocalcin participate in establishing reciprocal signal site of injury. The persistence of cbfa1 and ihh, and their targets osteocalcin and gli1, in the callus suggests comparable processes of chondrocyte maturation and specification of a neo-perichondrium occur following injury. VEGF and mmp13 are expressed during the later stages of healing, coincident with the onset of vascularization of the callus and subsequent ossification. Taken together, these data suggest the genetic mechanisms regulating fetal skeletogenesis also regulate adult skeletal regeneration, and point to important regulators of angiogenesis and ossification in bone regeneration.
骨形成是一个持续的过程，始于胎儿发育阶段，并作为一个重塑过程贯穿一生。在受伤时，骨骼通过生成新骨而非瘢痕组织来愈合；因此，它可以准确地被描述为一个再生过程。为了阐明胎儿骨骼发育与骨骼再生的相似程度，我们使用了一些调控软骨内成骨关键阶段的基因进行了一系列详细的表达分析。这些基因包括印度刺猬因子（ihh）和核心结合因子1（cbfa1）信号通路中的基因，以及与细胞外基质重塑和血管侵入相关的基因，包括血管内皮生长因子（VEGF）和基质金属蛋白酶13（mmp13）。我们的分析表明，即使在间充质细胞凝聚的最早阶段，软骨细胞（ihh、cbfa1和II型胶原阳性）和软骨膜细胞（gli1和骨钙素阳性）群体就已经确定。随着软骨细胞成熟，它们继续表达cbfa1和ihh，而cbfa1、骨钙素和gli1在假定的骨膜细胞中持续存在。后来，当软骨细胞经历肥大和终末分化时，VEGF和mmp13转录本在其中大量存在。基于这些表达模式和现有的遗传数据，我们提出了一个模型，其中Ihh和Cbfa1与Gli1和骨钙素一起参与建立损伤的相互信号位点。Cbfa1和ihh及其靶标骨钙素和gli1在骨痂中的持续存在表明，损伤后软骨细胞成熟和新软骨膜形成的过程具有可比性。VEGF和mmp13在愈合后期表达，与骨痂血管化和随后的骨化开始同时发生。综上所述，这些数据表明调控胎儿骨骼发生的遗传机制也调控成人骨骼再生，并指出了骨再生中血管生成和骨化的重要调节因子。
