Gerstenfeld L C, Cho T J, Kon T, Aizawa T, Tsay A, Fitch J, Barnes G L, Graves D T, Einhorn T A
Orthopaedics Research Laboratory, Department of Orthopaedic Surgery, Boston University Medical Center, Boston, Massachusetts 02118, USA.
J Bone Miner Res. 2003 Sep;18(9):1584-92. doi: 10.1359/jbmr.2003.18.9.1584.
TNF-alpha is a major inflammatory factor that is induced in response to injury, and it contributes to the normal regulatory processes of bone resorption. The role of TNF-alpha during fracture healing was examined in wild-type and TNF-alpha receptor (p55(-/-)/p75(-/-))-deficient mice. The results show that TNF-alpha plays an important regulatory role in postnatal endochondral bone formation.
TNF-alpha is a major inflammatory factor that is induced as part of the innate immune response to injury, and it contributes to the normal regulatory processes of bone resorption.
The role of TNF-alpha was examined in a model of simple closed fracture repair in wild-type and TNF-alpha receptor (p55(-/-)/p75(-/-))-deficient mice. Histomorphometric measurements of the cartilage and bone and apoptotic cell counts in hypertrophic cartilage were carried out at multiple time points over 28 days of fracture healing (n = 5 animals per time point). The expression of multiple mRNAs for various cellular functions including extracellular matrix formation, bone resorption, and apoptosis were assessed (triplicate polls of mRNAs).
In the absence of TNF-alpha signaling, chondrogenic differentiation was delayed by 2-4 days but subsequently proceeded at an elevated rate. Endochondral tissue resorption was delayed 2-3 weeks in the TNF-alpha receptor (p55(-/-)/p75(-/-))-deficient mice compared with the wild-type animals. Functional studies of the mechanisms underlying the delay in endochondral resorption indicated that TNF-alpha mediated both chondrocyte apoptosis and the expression of proresorptive cytokines that control endochondral tissue remodeling by osteoclasts. While the TNF-alpha receptor ablated animals show no overt developmental alterations of their skeletons, the results illustrate the primary roles that TNF-alpha function contributes to in promoting postnatal fracture repair as well as suggest that processes of skeletal tissue development and postnatal repair are controlled in part by differing mechanisms. In summary, these results show that TNF-alpha participates at several functional levels, including the recruitment of mesenchymal stem, apoptosis of hypertrophic chondrocytes, and the recruitment of osteoclasts function during the postnatal endochondral repair of fracture healing.
肿瘤坏死因子-α（TNF-α）是一种主要的炎症因子，在损伤反应中被诱导产生，并且它有助于骨吸收的正常调节过程。在野生型和肿瘤坏死因子-α受体（p55(-/-)/p75(-/-)）缺陷型小鼠中研究了TNF-α在骨折愈合过程中的作用。结果表明，TNF-α在出生后软骨内成骨过程中起重要的调节作用。
TNF-α是一种主要的炎症因子，作为对损伤的固有免疫反应的一部分被诱导产生，并且它有助于骨吸收的正常调节过程。
在野生型和肿瘤坏死因子-α受体（p55(-/-)/p75(-/-)）缺陷型小鼠的简单闭合性骨折修复模型中研究了TNF-α的作用。在骨折愈合的28天内的多个时间点对软骨和骨进行组织形态计量学测量，并对肥大软骨中的凋亡细胞进行计数（每个时间点n = 5只动物）。评估了包括细胞外基质形成、骨吸收和凋亡在内的多种细胞功能的多个mRNA的表达（mRNA的三次重复检测）。
在缺乏TNF-α信号传导的情况下，软骨形成分化延迟2 - 4天，但随后以升高的速率进行。与野生型动物相比，TNF-α受体（p55(-/-)/p75(-/-)）缺陷型小鼠的软骨内组织吸收延迟2 - 3周。对软骨内吸收延迟机制的功能研究表明，TNF-α介导软骨细胞凋亡以及控制破骨细胞对软骨内组织重塑的促吸收细胞因子的表达。虽然TNF-α受体缺失的动物未显示出其骨骼有明显的发育改变，但结果说明了TNF-α功能在促进出生后骨折修复中所起的主要作用，并且表明骨骼组织发育和出生后修复过程部分受不同机制控制。总之，这些结果表明，TNF-α在出生后骨折愈合的软骨内修复过程中参与了多个功能水平，包括间充质干细胞的募集、肥大软骨细胞的凋亡以及破骨细胞功能的募集。
