Bartlett Craig S, Rapuano Bruce E, Lorich Dean G, Wu Timothy, Anderson Richard C, Tomin Emre, Hsu John F, Lane Joseph M, Helfet David L
Department of Orthopaedic Surgery, University of Vermont Medical School, Burlington, VT 05401, USA.
Bone. 2006 Mar;38(3):322-32. doi: 10.1016/j.bone.2005.08.016. Epub 2005 Oct 12.
We have tested the hypothesis that the formation of heterotopic ossification (HO) in a rabbit model is correlated with a local increase in specific prostaglandins that may modulate mechanisms of ossification. Rabbits were sacrificed at 1 to 21 days following the daily forcible flexion of immobilized knees. The extraction and analysis of prostaglandins (PG) E2, F2alpha, D2, 6-keto-F1alpha, and thromboxane B2 in vastus intermedius muscles of manipulated legs revealed increases compared to control hindlimbs for all five prostaglandins, albeit of differing magnitude. The earliest increase was observed for PGF2alpha after 24 h (to 2.6-fold of control) with peak levels observed at day ten (185-fold of control). PGE2 was increased above control from 2 to 21 days following manipulation, with a peak level of 33-fold of control after 10 days. In a separate arm of the study, the role of PGE2 was investigated through the use of pharmacological antagonist of the PGE2 receptors and one of its second messengers, cAMP. Rabbits were preadministered the PGE2/PGD receptor antagonist AH 6809 or the cAMP antagonist Rp-cAMP prior to undergoing the regimen of limb immobilization and passive exercise. Both AH 6809 and Rp-cAMP were found to prevent the later development of radiographically documented heterotopic ossification in 15 out of 16 animals, thus identifying prostaglandins as being required for the development of ectopic bone. In this latter group, all but one pharmacologically treated animal showed an absence of HO at 3, 4, 5, or 6 weeks. These findings suggest an obligate cascade of prostaglandins for HO that offers the potential for novel prophylactic therapies, including those that target receptors for specific prostaglandins.
兔模型中异位骨化（HO）的形成与特定前列腺素的局部增加相关，这些前列腺素可能调节骨化机制。在每天强制固定膝关节屈曲后1至21天处死兔子。与对照后肢相比，对操作侧腿部股中间肌中前列腺素（PG）E2、F2α、D2、6-酮-F1α和血栓素B2的提取和分析显示，所有五种前列腺素均有增加，尽管增加幅度不同。最早在24小时后观察到PGF2α增加（至对照的2.6倍），在第10天观察到峰值水平（为对照的185倍）。操作后2至21天，PGE2高于对照水平，10天后峰值水平为对照的33倍。在该研究的另一个分支中，通过使用PGE2受体及其第二信使之一cAMP的药理学拮抗剂来研究PGE2的作用。在进行肢体固定和被动运动方案之前，给兔子预先施用PGE2/PGD受体拮抗剂AH 6809或cAMP拮抗剂Rp-cAMP。发现AH 6809和Rp-cAMP均能防止16只动物中的15只出现影像学记录的异位骨化，从而确定前列腺素是异位骨形成所必需的。在这后一组中，除一只接受药物治疗的动物外，所有动物在3、4、5或6周时均未出现HO。这些发现表明，HO形成过程中前列腺素存在必然的级联反应，这为新型预防性治疗提供了可能性，包括针对特定前列腺素受体的治疗。
