Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair
Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair
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DOI：
10.1172/jci200215681
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发表时间：
2002-06-01
影响因子：
15.9
通讯作者：
O'Keefe, RJ
中科院分区：
文献类型：
--
作者：
Zhang, XP;Schwarz, EM;O'Keefe, RJ
临床前。临床研究表明，环氧合酶可能在骨修复中发挥作用，并引发了人们对骨骼损伤患者使用非类固醇抗炎药物的担忧。我们利用野生型、COX-1(-/-)和COX-2(-/-)小鼠来证明COX-2在骨骼修复过程中的软骨内和膜内骨形成中发挥重要作用。与COX-1(-/-)和野生型对照组相比，COX-2(-/-)小鼠稳定的胫骨骨折愈合时间显著延迟。组织学特征是未分化间充质持续存在，成骨细胞生成显著减少，导致COX-2(-/-)小鼠高发生率的纤维性骨不连。类似地，与COX-1(-/-)或野生型小鼠相比，在活体注射成纤维细胞生长因子-1后，COX-2(-/-)小鼠颅盖骨的膜内骨形成减少了60%。为了阐明骨形成减少的机制，研究了从COX-2(-/-)和野生型小鼠获得的骨髓基质细胞培养的成骨细胞形成。COX-2-1-小鼠的骨结节形成减少了50%。在培养过程中加入前列腺素E_2(PGE(2))可完全修复成骨缺陷。在骨形态发生蛋白(BMP-2)存在的情况下，在对照组和COX-2(-/-)培养中，骨结节的形成与单独使用PGE2的水平相似，表明BMP弥补了COX-2的不足，位于前列腺素的下游。此外，我们发现COX-2(-/-)培养中的缺陷与cbfa1和osterix的水平显著降低有关，这两个基因是骨形成所必需的。PGE2的加入挽救了这一缺陷，而BMP-2在COX-2(-/-)和野生型培养中都增强了cbfa1和osterix。最后，这些药物的作用是相加的，表明COX-2参与了最大限度的成骨诱导。这些结果提供了一个模型，通过该模型，COX-2调节cbfa1和osterix的诱导，以介导正常的骨骼修复。
Preclinical. and clinical studies suggest a possible role for cyclooxygenases in bone repair and create concerns about the use of nonsteroidal antinflammatory drugs in patients with skeletal injury. We utilized wild-type, COX-1(-/-), and COX-2(-/-) mice to demonstrate that COX-2 plays an essential role in both endochondral and intramembranous bone formation during skeletal repair. The healing of stabilized tibia fractures was significantly delayed in COX-2(-/-) mice compared with COX-1(-/-) and wildtype controls. The histology was characterized by a persistence of undifferentiated mesenchyme and a marked reduction in osteoblastogenesis that resulted in a high incidence of fibrous nonunion in the COX-2(-/-) mice. Similarly, intramembranous bone formation on the calvaria was reduced 60% in COX-2(-/-) mice following in vivo injection of FGF-1 compared with either COX-1(-/-) or wild-type mice. To elucidate the mechanism involved in reduced bone formation, osteoblastogenesis was studied in bone marrow stromal cell cultures obtained from COX-2(-/-) and wild-type mice. Bone nodule formation was reduced 50% in COX-2-1-mice. The defect in osteogenesis was completely rescued by addition of prostaglandin E2 (PGE(2)) to the cultures. In the presence of bone morphogenetic protein (BMP-2), bone nodule formation was enhanced to a similar level above that observed with PGE2 alone in both control and COX-2(-/-) cultures, indicating that BMPs complement COX-2 deficiency and are downstream of prostaglandins. Furthermore, we found that the defect in COX-2(-/-) cultures correlated with significantly reduced levels of cbfa1 and osterix, two genes necessary for bone formation. Addition of PGE2 rescued this defect, while BMP-2 enhanced cbfa1 and osterix in both COX-2(-/-) and wildtype cultures. Finally, the effects of these agents were additive, indicating that COX-2 is involved in maximal induction of osteogenesis. These results provide a model whereby COX-2 regulates the induction of cbfa1 and osterix to mediate normal skeletal repair.